Tricyclic compounds as PARG inhibitors

Abstract

The present application provides tricyclic compounds of formula (I) that modulate the activity of poly(ADP-ribose) glycohydrolase (PARG), which are useful in the treatment of various diseases, including cancer.

Description

[0001] TRICYCLIC COMPOUNDS AS PARG INHIBITORS

[0002] TECHNICAL FIELD

[0003] The present disclosure provides tricyclic compounds as well as their pharmaceutical compositions that modulate the activity of poly(ADP-ribose) glycohydrolase (PARG) and are useful in the treatment of various diseases related to PARG, including cancer.

[0004] BACKGROUND

[0005] DNA repair or replication deficiency increases replication stress (RS) in cancer cells, inducing persistent DNA damage response (DDR) to stabilize replication forks and maintain genomic stability (Cybulla, E., et al., Nat Rev Cancer, 2023, 23, 6). As one of the hallmarks of cancer, RS leads to DNA breaks in S phase, triggers cell cycle checkpoints, eventually activates DNA repair or cell death pathways (Saxena, S., et al., Mol Cell, 2022, 82, 2298). Exploiting RS-related vulnerabilities by targeting DDR factors that cause additional DNA damage or prevent repair that exacerbates cellular stress emerges as an attractive strategy for treating cancers.

[0006] Development of highly potent, selective, and efficacious poly(ADP-ribose) glycohydrolase (PARG) inhibitors represents a promising avenue for targeted cancer therapy.

[0007] SUMMARY

[0008] The present disclosure provides, inter alia, compounds of Formula I: or pharmaceutically acceptable salts thereof, wherein constituent members are defined herein. The present disclosure further provides a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0009] The present disclosure further provides methods of inhibiting poly(ADP- ribose) glycohydrolase (PARG) activity, comprising contacting the PARG with a compound described herein, or a pharmaceutically acceptable salt thereof.

[0010] The present disclosure further provides methods of treating a disease or a disorder associated with PARG in a patient by administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof.

[0011] The present disclosure further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

[0012] The present disclosure further provides use of a compound described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein.

[0013] DETAILED DESCRIPTION

[0014] The present disclosure provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein:

[0015] = is a single or double bond; n is 0, 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6;

[0016] X is C or N;

[0017] Y is C or N; Z is O or NR4;

[0018] Ring A is phenyl, or 5-6 membered heteroaryl;

[0019] X1is N or CR5;

[0020] X2is N or CR6;

[0021] X3is N or CR7;

[0022] R1is selected from Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci- 4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci- 4 alkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0023] R2is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)- C1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each R2Ais independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, - ORa2A, -SRa2A, -NRc2ARd2A, -NO2, -C(O)Ra2A, -C(O)ORa2A, -C(O)NRc2ARd2A, - C(O)NRc2A(ORa2A), -OC(O)Ra2A, -OC(O)NRc2ARd2A, -OC(O)ORa2A, -OS(O)2Rb2A, - OS(O)2NRc2ARd2A, -NRc2AC(O)Ra2A, -NRc2AC(O)ORa2A, -NRc2AC(O)NRc2ARd2A, - NRc2AS(O)2Rb2A, -NRc2AS(O)2NRc2ARd2A, -NRc2AORa2A, -NRc2AS(O)Rb2A, - NRc2AS(O)NRc2ARd2A, -S(O)Rb2A, -S(O)2Rb2A, -S(O)NRc2ARd2A, -S(O)2NRc2ARd2A, - C(=NRe2A)Ra2A, -C(=NRe2A)NRc2ARd2A, -NRc2AC(=NRe2A)Ra2A, - NRc2AC(=NRe2A)NRc2ARd2A, -NRc2AS(O)(=NRe2A)Rb2A, - NRc2AS(O)(=NRe2A)NRc2ARd2A, -OS(O)(=NRe2A)Rb2A, -S(O)(=NRe2A)Rb2A, - S(O)(=NRe2A)NRc2ARd2A, -C(O)NRc2AS(O)2Rb2A, -C(O)NRc2AS(O)2NRc2ARd2A, - S(O)2NRc2AC(O)Rb2A, -NRc2AS(O)NRc2AC(O)Rb2A, and -P(O)Rf2ARg2A, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra2A, Rc2A, and Rd2Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra2A, Rc2A, and Rd2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc2Aand Rd2Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb2Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re2Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each RI2and Rg2Aare independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R3is independently selected from H, oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, -CN, -ORa3, -SRa3, -NRc3Rd3, -NO2, -C(O)Ra3, -C(O)ORa3, -C(O)NRc3Rd3, - S(O)2NRc3C(O)Rb3, -NRc3S(O)NRc3C(O)Rb3, and -P(O)RfiRg3, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Ra3, Rc3, and Rd3is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra3, Rc3, and Rd3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; or, any Rc3and Rd3attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Rb3is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Re3is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Rfiand Rg3are independently selected from H, C1-6 alkyl, C1-6 alkoxy, Ci- 6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R3Ais independently selected from oxo, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, - ORa3A, -SRa3A, -NRc3ARd3A, -NO2, -C(O)Ra3A, -C(O)ORa3A, -C(O)NRc3ARd3A, - C(O)NRc3A(ORa3A), -OC(O)Ra3A, -OC(O)NRc3ARd3A, -OC(O)ORa3A, -OS(O)2Rb3A, - OS(O)2NRc3ARd3A, -NRc3AC(O)Ra3A, -NRc3AC(O)ORa3A, -NRc3AC(O)NRc3ARd3A, - NRc3AS(O)2Rb3A, -NRc3AS(O)2NRc3ARd3A, -NRc3AORa3A, -NRc3AS(O)Rb3A, - NRc3AS(O)NRc3ARd3A, -S(O)Rb3A, -S(O)2Rb3A, -S(O)NRc3ARd3A, -S(O)2NRc3ARd3A, - C(=NRe3A)Ra3A, -C(=NRe3A)NRc3ARd3A, -NRc3AC(=NRe3A)Ra3A, - NRc3AC(=NRe3A)NRc3ARd3A, -NRc3AS(O)(=NRe3A)Rb3A, - NRc3AS(O)(=NRe3A)NRc3ARd3A, -OS(O)(=NRe3A)Rb3A, -S(O)(=NRe3A)Rb3A, - S(O)(=NRe3A)NRc3ARd3A, -C(O)NRc3AS(O)2Rb3A, -C(O)NRc3AS(O)2NRc3ARd3A, - S(O)2NRc3AC(O)Rb3A, -NRc3AS(O)NRc3AC(O)Rb3A, and -P(O)RfiARg3A, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra3A, Rc3A, and Rd3Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra3A, Rc3A, and Rd3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc3Aand Rd3Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb3Ais independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb3Aare each optionally substituted with 1, 2,

[0024] 3, 4, 5, or 6 independently selected RGsubstituents; each Re3Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each RfiAand Rg3Aare independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;

[0025] R4is selected from H, CN, ORa4, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of R4are each optionally substituted with 1, 2, 3,

[0026] 4, 5, or 6 independently selected RGsubstituents; or, R4and R1, together with the atoms to which they are attached, form a 5-10 membered heterocycloalkyl group, wherein the 5-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0027] Ra4is selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3- 10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)- C1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra4is each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0028] R5is selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and -CN;

[0029] R6is selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and -CN;

[0030] R7is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, - ORa7, -SRa7, -NRc7Rd7, -NO2, -C(O)Ra7, -C(O)ORa7, -C(O)NRc7Rd7, - C(O)NRc7(ORa7), -OC(O)Ra7, -OC(O)NRc7Rd7, -OC(O)ORa7, -OS(O)2Rb7, - OS(O)2NRc7Rd7, -NRc7C(O)Ra7, -NRc7C(O)ORa7, -NRc7C(O)NRc7Rd7, -NRc7S(O)2Rb7, -NRc7S(O)2NRc7Rd7, -NRc7ORa7, -NRc7S(O)Rb7, -NRc7S(O)NRc7Rd7, -S(O)Rb7, - S(O)2Rb7, -S(O)NRc7Rd7, -S(O)2NRc7Rd7, -C(=NRe7)Ra7, -C(=NRe7)NRc7Rd7, - NRc7C(=NRe7)Ra7, -NRc7C(=NRe7)NRc7Rd7, -NRc7S(O)(=NRe7)Rb7, - NRc7S(O)(=NRe7)NRc7Rd7, -OS(O)(=NRe7)Rb7, -S(O)(=NRe7)Rb7, - S(O)(=NRe7)NRc7Rd7, -C(O)NRc7S(O)2Rb7, -C(O)NRc7S(O)2NRc7Rd7, - S(O)2NRc7C(O)Rb7, -NRc7S(O)NRc7C(O)Rb7, and -P(O)RnRg7, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R7are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R7Asubstituents; each Ra7, Rc7, and Rd7is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra7, Rc7, and Rd7are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R7Asubstituents; or, any Rc7and Rd7attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R7Asubstituents; each Rb7is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb7are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R7Asubstituents; each Re7is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R17and Rg7are independently selected from H, Ci-6 alkyl, Ci-6 alkoxy, Ci- 6 haloalkyl, Ci-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R7Ais independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, - ORa7A, -SRa7A, -NRc7ARd7A, -NO2, -C(O)Ra7A, -C(O)ORa7A, -C(O)NRc7ARd7A, - C(O)NRc7A(ORa7A), -OC(O)Ra7A, -OC(O)NRc7ARd7A, -OC(O)ORa7A, -OS(O)2Rb7A, - OS(O)2NRc7ARd7A, -NRc7AC(O)Ra7A, -NRc7AC(O)ORa7A, -NRc7AC(O)NRc7ARd7A, - NRc7AS(O)2Rb7A, -NRc7AS(O)2NRc7ARd7A, -NRc7AORa7A, -NRc7AS(O)Rb7A, - NRc7AS(O)NRc7ARd7A, -S(O)Rb7A, -S(O)2Rb7A, -S(O)NRc7ARd7A, -S(O)2NRc7ARd7A, - C(=NRe7A)Ra7A, -C(=NRe7A)NRc7ARd7A, -NRc7AC(=NRe7A)Ra7A, - NRc7AC(=NRe7A)NRc7ARd7A, -NRc7AS(O)(=NRe7A)Rb7A, - NRc7AS(O)(=NRe7A)NRc7ARd7A, -OS(O)(=NRe7A)Rb7A, -S(O)(=NRe7A)Rb7A, - S(O)(=NRe7A)NRc7ARd7A, -C(O)NRc7AS(O)2Rb7A, -C(O)NRc7AS(O)2NRc7ARd7A, - S(O)2NRc7AC(O)Rb7A, -NRc7AS(O)NRc7AC(O)Rb7A, and -P(O)RnARg7A, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R7Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra7A, Rc7A, and Rd7Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra7A, Rc7A, and Rd7Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc7Aand Rd7Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb7Ais independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb7Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re7Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each RI7and Rg7Aare independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;

[0031] R8is selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and -CN;

[0032] R9is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, - ORa9, -SRa9, -NRc9Rd9, -NO2, -C(O)Ra9, -C(O)ORa9, -C(O)NRc9Rd9, - S(O)2NRc9C(O)Rb9, -NRc9S(O)NRc9C(O)Rb9, and -P(O)R®Rg9, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R9are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R9Asubstituents; each Ra9, Rc9, and Rd9is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra9, Rc9, and Rd9are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R9Asubstituents; or, any Rc9and Rd9attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R9Asubstituents; each Rb9is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb9are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R9Asubstituents; each Re9is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl,

[0033] 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R® and Rg9are independently selected from H, C1-6 alkyl, C1-6 alkoxy, Ci- 6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R9Ais independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl,

[0034] 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, - ORa9A, -SRa9A, -NRc9ARd9A, -NO2, -C(O)Ra9A, -C(O)ORa9A, -C(O)NRc9ARd9A, - C(O)NRc9A(ORa9A), -OC(O)Ra9A, -OC(O)NRc9ARd9A, -OC(O)ORa9A, -OS(O)2Rb9A, - OS(O)2NRc9ARd9A, -NRc9AC(O)Ra9A, -NRc9AC(O)ORa9A, -NRc9AC(O)NRc9ARd9A, - NRc9AS(O)2Rb9A, -NRc9AS(O)2NRc9ARd9A, -NRc9AORa9A, -NRc9AS(O)Rb9A, - NRc9AS(O)NRc9ARd9A, -S(O)Rb9A, -S(O)2Rb9A, -S(O)NRc9ARd9A, -S(O)2NRc9ARd9A, - C(=NRe9A)Ra9A, -C(=NRe9A)NRc9ARd9A, -NRc9AC(=NRe9A)Ra9A, - NRc9AC(=NRe9A)NRc9ARd9A, -NRc9AS(O)(=NRe9A)Rb9A, - NRc9AS(O)(=NRe9A)NRc9ARd9A, -OS(O)(=NRe9A)Rb9A, -S(O)(=NRe9A)Rb9A, - S(O)(=NRe9A)NRc9ARd9A, -C(O)NRc9AS(O)2Rb9A, -C(O)NRc9AS(O)2NRc9ARd9A, - S(O)2NRc9AC(O)Rb9A, -NRc9AS(O)NRc9AC(O)Rb9A, and -P(O)R®ARg9A, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R9Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra9A, Rc9A, and Rd9Ais independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra9A, Rc9A, and Rd9Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc9Aand Rd9Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb9Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb9Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re9Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R®Aand Rg9Aare independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R10is independently selected from H, oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, -CN, -ORal°, -SRal°, -NRcl0Rdl°, -NO2, -C(O)Ral°, -C(O)ORal°, - C(O)NRcl0Rdl°, -C(O)NRcl0(ORal°), -OC(O)Ral°, -OC(O)NRcl0Rdl°, -OC(O)ORal°, - OS(O)2Rbl°, -OS(O)2NRcl0Rd10, -NRcl0C(O)Ral°, -NRcl0C(O)ORal°, - NRcl0C(O)NRcl0Rdl°, -NRcl0S(O)2Rbl°, -NRcl0S(O)2NRcl0Rdl°, -NRcl0ORal°, - NRcl0S(O)Rbl°, -NRcl0S(O)NRcl0Rdl°, -S(O)Rbl°, -S(O)2Rbl°, -S(O)NRcl0Rdl°, - S(O)2NRcl0Rd10, -C(=NRel0)Ral°, -C(=NRel0)NRcl0Rdl°, -NRcl0C(=NRel0)Ral°, - NRcl0C(=NRel0)NRcl0Rdl°, -NRcl0S(O)(=NRel0)Rbl°, -NRcl0S(O)(=NRel0)NRcl0Rd10, - OS(O)(=NRel0)Rbl°, -S(O)(=NRel0)Rbl°, -S(O)(=NRel0)NRcl0Rdl°, - C(O)NRcl0S(O)2Rbl°, -C(O)NRcl0S(O)2NRcl0Rdl°, -S(O)2NRcl0C(O)Rb10, - NRcl0S(O)NRcl0C(O)Rbl°, and -P(O)Rfl0Rgl°, wherein the Ci-6alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R10are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R10Asubstituents; or, two R10, together with the atoms to which they are attached, form a C3-10 cycloalkyl, or 4-10 membered heterocycloalkyl group, wherein the C3-10 cycloalkyl and 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R10Asubstituents; each Ral°, Rcl°, and Rdl° is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ral°, Rcl°, and Rdl° are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R10Asubstituents; or, any Rcl° and Rdl° attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R10Asubstituents; each Rbl° is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rbl° are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R10Asubstituents; each Rel° is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Rfl° and Rgl° are independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl,

[0035] 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R1OAis independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl,

[0036] 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, - ORal0A, -SRal0A, -NRcl0ARdl0A, -NO2, -C(O)Ral0A, -C(O)ORal0A, -C(O)NRcl0ARdl0A, - NRcl0AS(O)NRcl0AC(O)Rbl0A, and -P(O)Rfl0ARgl0A, wherein the Ci-6alkyl, C2.6alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R10Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ral0A, Rcl0A, and Rdl0Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ral0A, RCWA,an(j pdioAare eac 0pp0naiiy substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any RC10Aand Rdl0Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rbl0Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rbl0Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rel0Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl,

[0037] 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Rfl0Aand Rgl0Aare independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce- 10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl; each R11is independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl,

[0038] 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, - ORa11, -SRa11, -NRcl lRd11, -NO2, -C(O)Ra11, -C(O)ORa11, -C(O)NRcllRd11, - C(O)NRcl l(ORa11), -OC(O)Ra11, -OC(O)NRcl lRd11, -OC(O)ORa11, -OS(O)2Rb11, - OS(O)2NRcllRd11, -NRcl lC(O)Ra11, -NRcllC(O)ORa11, -NRcl lC(O)NRcllRd11, - NRcllS(O)2Rb11, -NRcl lS(O)2NRcllRd11, -NRcl lORa11, -NRcl lS(O)Rb11, - NRcllS(O)NRcl lRd11, -S(O)Rb11, -S(O)2Rb11, -S(O)NRcl lRd11, -S(O)2NRcllRd11, - C(=NRel l)Ra11, -C(=NRel l)NRcllRd11, -NRcl lC(=NRel l)Ra11, - NRcllC(=NRel l)NRcllRd11, -NRcl lS(O)(=NRel l)Rb11, -NRcl lS(O)(=NRel l)NRcl lRd11, - OS(O)(=NRel l)Rb11, -S(O)(=NRel l)Rb11, -S(O)(=NRell)NRcl lRd11, - C(O)NRcl lS(O)2Rbn, -C(O)NRcl lS(O)2NRcl lRd11, -S(O)2NRcllC(O)Rb11, - NRcllS(O)NRcl lC(O)Rb11, and -P(O)Rfl lRg11, wherein the Ci-6alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R11are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R11Asubstituents; or, R4and one of R11, together with the atoms to which they are attached, form a 5-10 membered heterocycloalkyl group, wherein the 5-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R11Asubstituents; or, R1and one of R11, together with the atoms to which they are attached, form a 5-10 membered heterocycloalkyl group, wherein the 5-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R11Asubstituents; or, two R11, together with the atoms to which they are attached, form a C3-10 cycloalkyl, or 4-10 membered heterocycloalkyl group, wherein the C3-10 cycloalkyl and 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R11Asubstituents; each Ral 1, Rcl 1, and Rdl 1is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ral1, Rcl 1, and Rdl 1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R11Asubstituents; or, any Rcl 1and Rdl 1attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R11Asubstituents; each Rbl 1is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rbl1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R11Asubstituents; each Rel 1is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Rfl 1and Rgl 1are independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl,

[0039] 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R11Ais independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl,

[0040] 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, - ORallA, -SRallA, -NRcl lARdl lA, -NO2, -C(O)Ral lA, -C(O)ORal lA, -C(O)NRcl lARdl lA, - C(O)NRcl lA(ORallA), -OC(O)Ral lA, -OC(O)NRcllARdl lA, -OC(O)ORal lA, - OS(O)2Rbl lA, -OS(O)2NRcllARdl lA, -NRcl lAC(O)RallA, -NRcl lAC(O)ORal lA, - NRcllAC(O)NRcl lARdllA, -NRcllAS(O)2Rbl lA, -NRcllAS(O)2NRcl lARdllA, - NRcllAORallA, -NRcllAS(O)Rbl lA, -NRcllAS(O)NRcl lARdllA, -S(O)Rbl lA, -S(O)2Rbl lA, -S(O)NRcl lARdl lA, -S(O)2NRcl lARdllA, -C(=NRel lA)Ral lA, -C(=NRellA)NRcl lARdl lA, - NRcllAC(=NRellA)RallA, -NRcl lAC(=NRel lA)NRcllARdl lA, - NRcllAS(O)(=NRel lA)RbllA, -NRcl lAS(O)(=NRellA)NRcl lARdllA, - OS(O)(=NRel lA)Rbl lA, -S(O)(=NRel lA)Rbl lA, -S(O)(=NRel lA)NRcl lARdllA, - C(O)NRcl lAS(O)2RbllA, -C(O)NRcl lAS(O)2NRcllARdl lA, -S(O)2NRcl lAC(O)Rbl lA, - NRcllAS(O)NRcllAC(O)Rbl lA, and -P(O)Rfl lARgllA, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R11Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ral lA, Rcl lA, and Rdl lAis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of RallA, RC11A, and RdllAare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any RC11Aand RdllAattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rbl lAis independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of RbllAare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rel lAis independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Rfl lAand Rgl lAare independently selected from H, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce- 10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl; each RGis independently selected from OH, CN, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-Ci-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-3 alkylamino, di(Ci-3 alkyl)amino, thio, C1-3 alkylthio, C1-3 alkylsulfinyl, Ci- 3 alkyl sulfonyl, carbamyl, C1-3 alkylcarbamyl, di(Ci-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxy carbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di (C 1-3 alkyl)aminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(Ci-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di (C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di(Ci-3 alkyl)aminocarbonylamino.

[0041] In some embodiments, = is a single bond.

[0042] In some embodiments, = is a double bond.

[0043] In some embodiments, X is N.

[0044] In some embodiments, X is C.

[0045] In some embodiments, Y is N.

[0046] In some embodiments, Y is C.

[0047] In some embodiments, X is N and Y is C.

[0048] In some embodiments, Z is O.

[0049] In some embodiments, Z is NR4.

[0050] In some embodiments:

[0051] X is N or C;

[0052] Y is C; and

[0053] Z is O.

[0054] In some embodiments:

[0055] X is N;

[0056] Y is C; and Z is O.

[0057] In some embodiments,

[0058] In some embodiments,

[0059] In some embodiments, X1is CR5.

[0060] In some embodiments, R5is selected from H and C1-4 alkyl.

[0061] In some embodiments, R5is H.

[0062] In some embodiments, X2is CR6.

[0063] In some embodiments, R6is selected from H and C1-4 alkyl.

[0064] In some embodiments, R6is H.

[0065] In some embodiments, X3is CR7.

[0066] In some embodiments:

[0067] X1is CR5;

[0068] X2is CR6; and

[0069] X3is CR7.

[0070] In some embodiments,

[0071] In some embodiments,

[0072] In some embodiments, R7is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R7are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R7Asubstituents. In some embodiments, R7is selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R7are each optionally substituted with 1, 2, 3, or 4, 5, or 6 independently selected R7Asubstituents.

[0073] In some embodiments, R7is selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, and 5-6 membered heteroaryl of R7are each optionally substituted with 1, 2, 3, or 4 independently selected R7Asubstituents.

[0074] In some embodiments, R7is selected from H, halo, C1-6 alkyl, C3-7 cycloalkyl, phenyl, monocyclic 4-7 membered heterocycloalkyl, and spirocyclic 8-10 membered heterocycloalkyl wherein the C1-6 alkyl, C3-7 cycloalkyl, phenyl, monocyclic 4-7 membered heterocycloalkyl, and spirocyclic 8-10 membered heterocycloalkyl of R7are each optionally substituted with 1, 2, 3, or 4 independently selected R7Asubstituents.

[0075] In some embodiments, R7is selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of R7are each optionally substituted with 1, 2, 3, or 4 independently selected R7Asubstituents.

[0076] In some embodiments, R7is selected from halo, C1-6 alkyl, and Ce-io aryl, wherein the C1-6 alkyl and Ce-io aryl of R7are each optionally substituted with 1, 2, 3, or 4 independently selected R7Asubstituents.

[0077] In some embodiments, R7is selected from halo, C1-6 alkyl, and phenyl, wherein the C1-6 alkyl and phenyl of R7are each optionally substituted with 1, 2, 3, or 4 independently selected R7Asubstituents.

[0078] In some embodiments, R7is selected from halo, C1-6 alkyl, and phenyl, wherein the C1-6 alkyl of R7is optionally substituted with 1, 2, 3, or 4 independently selected R7Asubstituents. In some embodiments, R7is selected from H, fluoro, chloro, bromo, methyl, cyclohexenyl, phenyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, 4,7- di azaspiro [2.5 ]octanyl, and 2-oxa-7-azaspiro[3.5]nonanyl, wherein the methyl, cyclohexenyl, phenyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, 4,7- di azaspiro [2.5 ]octanyl, and 2-oxa-7-azaspiro[3.5]nonanyl of R7are each optionally substituted with 1, 2, 3, or 4 independently selected R7Asubstituents.

[0079] In some embodiments, R7is selected from H, fluoro, chloro, bromo, methyl, cyclohexenyl, phenyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, 4,7- di azaspiro [2.5 ]octanyl, and 2-oxa-7-azaspiro[3.5]nonanyl, wherein the methyl, cyclohexenyl, phenyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, 4,7- di azaspiro [2.5 ]octanyl, and 2-oxa-7-azaspiro[3.5]nonanyl of R7are each optionally substituted with 1 or 2 independently selected R7Asubstituents.

[0080] In some embodiments, R7is selected from bromo, methyl, and phenyl, wherein the methyl and phenyl of R7are each optionally substituted with 1 or 2 independently selected R7Asubstituents.

[0081] In some embodiments, R7is selected from bromo, methyl, and phenyl, wherein the methyl of R7is optionally substituted with 1 or 2 independently selected R7Asubstituents.

[0082] In some embodiments, each R7Ais independently selected from Ci-6 alkyl, 4- 10 membered heterocycloalkyl, -C(O)Ra7A, -C(O)NRc7ARd7A, NRc7ARd7A, - NRc7AC(O)Ra7A, -NRc7AC(O)ORa7A, -NRc7AC(O)NRc7ARd7A, -NRc7AS(O)2Rb7A, - NRc7AS(O)2NRc7ARd7A, -NRc7AORa7A, -NRc7AS(O)Rb7A, -NRc7AS(O)NRc7ARd7A, - NRc7AC(=NRe7A)Ra7A, -NRc7AC(=NRe7A)NRc7ARd7A, -NRc7AS(O)(=NRe7A)Rb7A, - NRc7AS(O)(=NRe7A)NRc7ARd7A, and -NRc7AS(O)NRc7AC(O)Rb7A, wherein the Ci-6alkyl and 4-10 membered heterocycloalkyl of R7Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents.

[0083] In some embodiments, each R7Ais independently selected from Ci-6 alkyl, 4- 10 membered heterocycloalkyl, -C(O)Ra7A, -C(O)NRc7ARd7A, NRc7ARd7A, - NRc7AC(O)Ra7A, -NRc7AC(O)ORa7A, -NRc7AC(O)NRc7ARd7A, -NRc7AS(O)2Rb7A, - NRc7AS(O)2NRc7ARd7A, -NRc7AORa7A, -NRc7AS(O)Rb7A, -NRc7AS(O)NRc7ARd7A, - NRc7AC(=NRe7A)Ra7A, -NRc7AC(=NRe7A)NRc7ARd7A, -NRc7AS(O)(=NRe7A)Rb7A, - NRc7AS(O)(=NRe7A)NRc7ARd7A, and -NRc7AS(O)NRc7AC(O)Rb7A, wherein the Ci-6 alkyl and 4-10 membered heterocycloalkyl of R7Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

[0084] In some embodiments, each R7Ais independently selected from NRc7ARd7A, - NRc7AC(O)Ra7A, -NRc7AC(O)ORa7A, -NRc7AC(O)NRc7ARd7A, -NRc7AS(O)2Rb7A, - NRc7AS(O)2NRc7ARd7A, -NRc7AORa7A, -NRc7AS(O)Rb7A, -NRc7AS(O)NRc7ARd7A, - NRc7AC(=NRe7A)Ra7A, -NRc7AC(=NRe7A)NRc7ARd7A, -NRc7AS(O)(=NRe7A)Rb7A, - NRc7AS(O)(=NRe7A)NRc7ARd7A, and -NRc7AS(O)NRc7AC(O)Rb7A

[0085] In some embodiments, each R7Ais independently selected from Ci-6 alkyl, 4-7 membered heterocycloalkyl, -C(O)Ra7A, -C(O)NRc7ARd7A, and NRc7ARd7A, wherein the Ci-6 alkyl and 4-7 membered heterocycloalkyl of R7Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

[0086] In some embodiments, each R7Ais independently selected from NRc7ARd7A.

[0087] In some embodiments, each Ra7A, Rc7A, and Rd7Ais independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of Ra7A, Rc7A, and Rd7Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents.

[0088] In some embodiments, each Ra7A, Rc7A, and Rd7Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of Ra7A, Rc7A, and Rd7Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

[0089] In some embodiments, each Rc7Aand Rd7Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of Rc7Aand Rd7Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents. In some embodiments, each Rc7Aand Rd7Ais independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of Rc7Aand Rd7Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

[0090] In some embodiments, each Rc7Aand Rd7Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C1-6 alkyl, Ci- 6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of Rc7Aand Rd7Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

[0091] In some embodiments, each Ra7A, Rc7A, and Rd7Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl of Ra7A, Rc7A, and Rd7Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

[0092] In some embodiments, each Ra7A, Rc7A, and Rd7Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, and 4-7 membered heterocycloalkyl, the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, and 4-7 membered heterocycloalkyl of Ra7A, RC7A, and Rd7Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

[0093] In some embodiments, each Rc7Aand Rd7Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, and C3-10 cycloalkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, and C3-10 cycloalkyl of Rc7Aand Rd7Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

[0094] In some embodiments, each Rc7Aand Rd7Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, and C3-10 cycloalkyl.

[0095] In some embodiments, each Rc7Aand Rd7Ais independently selected from C1-6 alkyl and C3-10 cycloalkyl.

[0096] In some embodiments, each Rc7Aand Rd7Ais independently selected from C1-6 alkyl and C3-7 cycloalkyl. In some embodiments, each Rc7Aand Rd7Ais independently selected from C1-3 alkyl and C3-7 cycloalkyl.

[0097] In some embodiments, each Ra7A, Rc7A, and Rd7Ais independently selected from methyl, isopropyl, fluoroisopropyl, cyclopropyl, and morpholinyl, wherein the methyl, isopropyl, fluoroisopropyl, cyclopropyl, and morpholinyl of Ra7A, Rc7A, and Rd7Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

[0098] In some embodiments, each Rc7Aand Rd7Ais independently selected from methyl and cyclopropyl.

[0099] In some embodiments, each R7Ais independently selected from (cyclopropyl)(methyl)amino.

[0100] In some embodiments:

[0101] R7is selected from H, halo, C1-6 alkyl, C3-7 cycloalkyl, phenyl, monocyclic 4-7 membered heterocycloalkyl, and spirocyclic 8-10 membered heterocycloalkyl wherein the C1-6 alkyl, C3-7 cycloalkyl, phenyl, monocyclic 4-7 membered heterocycloalkyl, and spirocyclic 8-10 membered heterocycloalkyl of R7are each optionally substituted with 1, 2, 3, or 4 independently selected R7Asubstituents; each R7Ais independently selected from C1-6 alkyl, 4-7 membered heterocycloalkyl, -C(O)Ra7A, -C(O)NRc7ARd7A, and NRc7ARd7A, wherein the C1-6 alkyl and 4-7 membered heterocycloalkyl of R7Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; and each Ra7A, Rc7A, and Rd7Ais independently selected from methyl, isopropyl, fluoroisopropyl, cyclopropyl, and morpholinyl, wherein the methyl, isopropyl, fluoroisopropyl, cyclopropyl, and morpholinyl of Ra7A, Rc7A, and Rd7Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

[0102] In some embodiments, R7is selected from halo, C1-6 alkyl, and Ce-io aryl, wherein the C1-6 alkyl is optionally substituted with one R7Asubstituent which isNRC7ARd7A.andeach RC7Aand Rd7Ais independently selected from C1-3 alkyl and C3-7 cycloalkyl. In some embodiments, R7is selected from halo, Ci-6 alkyl, and phenyl, wherein the Ci-6 alkyl is optionally substituted with one R7Asubstituent which is NR^ARdVA.andeach RC7Aand Rd7Ais independently selected from C1-3 alkyl and C3-7 cycloalkyl.

[0103] In some embodiments, R7is selected from bromo, methyl, and phenyl, wherein the methyl is optionally substituted with one R7Asubstituent which is NR^ARdVA.andeach RC7Aand Rd7Ais independently selected from C1-3 alkyl and C3-7 cycloalkyl.

[0104] In some embodiments, R7is selected from bromo, methyl, and phenyl, wherein the methyl is optionally substituted with one R7Asubstituent which is (cyclopropyl)(methyl)amino.

[0105] In some embodiments, R7is selected from H, fluoro, chloro, bromo, methyl, cyclohexenyl, phenyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, 4,7- di azaspiro [2.5 ]octanyl, and 2-oxa-7-azaspiro[3.5]nonanyl, wherein the methyl, cyclohexenyl, phenyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, 4,7- di azaspiro [2.5 ]octanyl, and 2-oxa-7-azaspiro[3.5]nonanyl of R7are each optionally substituted with 1 or 2 independently selected R7Asubstituents; each R7Ais independently selected from C1-6 alkyl, 4-7 membered heterocycloalkyl, -C(O)Ra7A, -C(O)NRc7ARd7A, and NRc7ARd7A, wherein the C1-6 alkyl and 4-7 membered heterocycloalkyl of R7Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; and each Ra7A, Rc7A, and Rd7Ais independently selected from methyl, isopropyl, fluoroisopropyl, cyclopropyl, and morpholinyl, wherein the methyl, isopropyl, fluoroisopropyl, cyclopropyl, and morpholinyl of Ra7A, Rc7A, and Rd7Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

[0106] In some embodiments, R7is selected from H, fluoro, chloro, bromo, methyl,

[0107]

[0108] In some embodiments, R7is selected from H, fluoro, chloro, bromo, methyl,

[0109]

[0110] In some embodiments, R7is selected from bromo, methyl, and phenyl, wherein the methyl is substituted with one R7Asubstituent which is (cyclopropyl)(methyl)amino.

[0111] In some embodiments, R1is selected from C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci- 4 alkyl, wherein the C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl- C1-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents.

[0112] In some embodiments, R1is selected from C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci- 4 alkyl, wherein the C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl- C1-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl of R1are each optionally substituted with 1 or 2 independently selected RGsubstituents.

[0113] In some embodiments, R1is selected from C3-6 cycloalkyl and C3-6 cycloalkyl- C1-4 alkyl, wherein the C3-6 cycloalkyl and C3-6 cycloalkyl-Ci-4 alkyl of R1are each optionally substituted with 1 or 2 independently selected RGsubstituents.

[0114] In some embodiments, R1is C3-6 cycloalkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

[0115] In some embodiments, R1is C3-6 cycloalkyl, which is optionally substituted with 1 or 2 independently selected RGsubstituents.

[0116] In some embodiments, R1is cyclopropyl, which is optionally substituted with 1 or 2 independently selected RGsubstituents. In some embodiments, R1is cyclopropyl, which is optionally substituted with

[0117] 1 RGsubstituent.

[0118] In some embodiments, each RGis independently selected from CN, halo, Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, cyano-Ci-4 alkyl, HO-C1-4 alkyl, and di(Ci-3 alkyl)amino.

[0119] In some embodiments, each RGis independently selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, and HO-C1-4 alkyl.

[0120] In some embodiments, each RGis independently selected from CN, halo, C1-4 alkyl, C1-4 alkoxy, and di(Ci-3 alkyl)amino.

[0121] In some embodiments, each RGis independently selected from C1-4 alkyl and C1-4 haloalkyl.

[0122] In some embodiments, each RGis independently selected from C1-4 alkyl.

[0123] In some embodiments, each RGis fluoro, CN, methyl, methoxy, and dimethylamino.

[0124] In some embodiments, each RGis methyl.

[0125] In some embodiments, Ring A is 5-6 membered heteroaryl.

[0126] In some embodiments, Ring A is 5-membered heteroaryl.

[0127] In some embodiments, Ring A is selected from pyrazolyl, imidazolyl, and triazolyl.

[0128] In some embodiments, Ring A is an imidazolyl ring.

[0129] In some embodiments, Ring A is an pyrazolyl ring.

[0130] In some embodiments, Ring A is a triazolyl ring.

[0131] In some embodiments, n is 0, 1, or 2.

[0132] In some embodiments, n is 0 or 1.

[0133] In some embodiments, n is 1 or 2.

[0134] In some embodiments, n is 1.

[0135] In some embodiments, n is 0.

[0136] In some embodiments, Ring A is selected from In some embodiments, each R3is independently selected from Ci-6 alkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, C6-io aryl-Ci-4 alkyl, -C(O)Ra3, -C(O)ORa3, -C(O)NRc3Rd3, -C(O)NRc3(ORa3), - S(O)2NRc3C(O)Rb3, -NRc3S(O)NRc3C(O)Rb3, and -P(O)RfiRg3, wherein the Ci-6alkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, and Ce-io aryl -C 1-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents.

[0137] In some embodiments, each R3is independently selected from -C(O)Ra3, -

[0138] In some embodiments, each R3is independently selected from halo, C1-6 alkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, C6-io aryl-Ci-4 alkyl, -C(O)Ra3, -C(O)ORa3, and -C(O)NRc3Rd3, wherein the Ci-6alkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, and Ce-io aryl-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, or 4 independently selected R3Asubstituents.

[0139] In some embodiments, each R3is independently selected from halo, Ci-6 alkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, (phenyl)-Ci-4 alkyl and -C(O)NRc3Rd3, wherein the Ci-6 alkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, and (phenyl)- C1-4 alkyl of R3are each optionally substituted with 1, 2, 3, or 4 independently selected R3Asubstituents.

[0140] In some embodiments, each R3is independently selected from halo, -C(O)Ra3, -C(O)ORa3, and -C(O)NRc3Rd3.

[0141] In some embodiments, each R3is independently selected from halo and - C(O)NRc3Rd3.

[0142] In some embodiments, each Ra3, Rb3, Rc3, and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl.

[0143] In some embodiments, each Rc3and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl.

[0144] In some embodiments, each Rc3and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl.

[0145] In some embodiments, each Rc3and Rd3is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl-Ci-4 alkyl, and Ce-io aryl-Ci-4 alkyl.

[0146] In some embodiments: each Rc3is independently selected from C1-6 alkyl, C3-10 cycloalkyl-Ci-4 alkyl, and Ce-io aryl-Ci-4 alkyl; and each Rd3is H.

[0147] In some embodiments, each Rc3and Rd3is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl-Ci-4 alkyl, and phenyl-Ci-4 alkyl.

[0148] In some embodiments: each Rc3is independently selected from C1-6 alkyl, C3-7 cycloalkyl-Ci-4 alkyl, and phenyl-Ci-4 alkyl; and each Rd3is H.

[0149] In some embodiments, each Rc3and Rd3is independently selected from H, methyl, cyclopropylmethyl, and phenylmethyl.

[0150] In some embodiments: each Rc3is independently selected from methyl, cyclopropylmethyl, and phenylmethyl; and each Rd3is H.

[0151] In some embodiments, each R3Ais independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C1-6 haloalkyl.

[0152] In some embodiments, each R3Ais independently selected from C1-6 alkyl.

[0153] In some embodiments, each R3Ais independently selected from C1-3 alkyl.

[0154] In some embodiments, each R3Ais methyl.

[0155] In some embodiments, each R3is independently selected from methyl, ethyl, isobutyl, iodo, cyclohexylmethyl, cyclohexylethyl, benzyl, methylpiperidinyl, methylpyrazolyl,

[0156] In some embodiments, each R3is independently selected from iodo, /

[0157] In some embodiments, each R3is iodo.

[0158] In some embodiments, each R3is I In some embodiments, each

[0159] In some embodiments, each

[0160] In some embodiments: n is i; and R3is iodo.

[0161] In some embodiments: n is i; and

[0162] In some embodiments: n is 1; and

[0163] In some embodiments: n is i; and

[0164] In some embodiments, R2is selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents.

[0165] In some embodiments, R2is selected from C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4- 10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents.

[0166] In some embodiments, R2is selected from C3-7 cycloalkyl-Ci-4 alkyl, phenyl- C1-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl, wherein the C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents.

[0167] In some embodiments, R2is (5-10 membered heteroaryl)-Ci-4 alkyl, which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents.

[0168] In some embodiments, R2is (5-10 membered heteroaryl)-Ci-4 alkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0169] In some embodiments, R2is (5-6 membered heteroaryl)-Ci-4 alkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0170] In some embodiments, R2is (5-membered heteroaryl)-Ci-4 alkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0171] In some embodiments, R2is (5-membered heteroaryl)-Ci-4 alkyl, which is optionally substituted with 1 or 2 independently selected R2Asubstituents.

[0172] In some embodiments, R2is selected from pyrazolylmethyl, thiazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, and oxadiazolylmethyl, wherein the pyrazolylmethyl, thiazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, and oxadiazolylmethyl of R2are each optionally substituted with 1 or 2 independently selected R2Asubstituents. In some embodiments, R2is pyrazolylmethyl, which is optionally substituted with 1 or 2 independently selected R2Asubstituents.

[0173] In some embodiments, each R2Ais independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-e alkynyl, and C1-6 haloalkyl.

[0174] In some embodiments, each R2Ais independently selected from C1-6 alkyl, and C1-6 haloalkyl.

[0175] In some embodiments, each R2Ais independently selected from C1-4 alkyl and C1-4 haloalkyl.

[0176] In some embodiments, each R2Ais independently selected from C1-6 alkyl.

[0177] In some embodiments, each R2Ais independently selected from C1-3 alkyl.

[0178] In some embodiments, each R2Ais independently selected from methyl, tertbutyl, and difluorom ethyl.

[0179] In some embodiments, each R2Ais methyl.

[0180] In some embodiments, R2is independently selected from

[0181] In some embodiments:

[0182] = is a single or double bond; n is 0, 1, or 2;

[0183] X is C or N;

[0184] Y is C or N;

[0185] Z is O;

[0186] X1is CR5;

[0187] X2is CR6;

[0188] X3is CR7; Ring A is phenyl or 5-6 membered heteroaryl;

[0189] R1is selected from C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl, wherein the C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0190] R2is selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each R2Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; each R3is independently selected from C1-6 alkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, -C(O)Ra3, -C(O)ORa3, -C(O)NRc3Rd3, -C(O)NRc3(ORa3), -OC(O)Ra3, - P(O)RfiRg3, wherein the C1-6 alkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, and Ce-io aryl-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Ra3, Rc3, and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; or, any Rc3and Rd3attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group; each Rb3is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Re3is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Rfiand Rg3are independently selected from H, C1-6 alkyl, C1-6 alkoxy, Ci- 6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R3Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl;

[0191] R5is selected from H and C1-4 alkyl;

[0192] R6is selected from H and C1-4 alkyl;

[0193] R7is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R7are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R7Asubstituents; each R7Ais independently selected from C1-6 alkyl, 4-10 membered heterocycloalkyl, -C(O)Ra7A, -C(O)NRc7ARd7A, NRc7ARd7A, -NRc7AC(O)Ra7A, - NRc7AC(O)ORa7A, -NRc7AC(O)NRc7ARd7A, -NRc7AS(O)2Rb7A, -NRc7AS(O)2NRc7ARd7A, -NRc7AORa7A, -NRc7AS(O)Rb7A, -NRc7AS(O)NRc7ARd7A, -NRc7AC(=NRe7A)Ra7A, - NRc7AC(=NRe7A)NRc7ARd7A, -NRc7AS(O)(=NRe7A)Rb7A, - NRc7AS(O)(=NRe7A)NRc7ARd7A, and -NRc7AS(O)NRc7AC(O)Rb7A, wherein the Ci-6alkyl and 4-10 membered heterocycloalkyl of R7Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra7A, Rc7A, and Rd7Ais independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; or, any Rc7Aand Rd7Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group; each Rb7Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Re7Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; and each RGis independently selected from OH, CN, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-Ci-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-3 alkylamino, di(Ci-3 alkyl)amino, thio, C1-3 alkylthio, C1-3 alkylsulfinyl, Ci- 3 alkyl sulfonyl, carbamyl, C1-3 alkylcarbamyl, di(Ci-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxy carbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di (C 1-3 alkyl)aminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(Ci-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di (C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di(Ci-3 alkyl)aminocarbonylamino.

[0194] In some embodiments: = is a single or double bond; n is 0, 1, or 2;

[0195] X is C or N;

[0196] Y is C or N;

[0197] Z is O;

[0198] X1is CR5;

[0199] X2is CR6;

[0200] X3is CR7;

[0201] Ring A is phenyl or 5-6 membered heteroaryl;

[0202] R1is selected from C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl, wherein the C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0203] R2is selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each R2Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; each R3is independently selected from -C(O)Ra3, -C(O)ORa3, -C(O)NRc3Rd3, - each Ra3, Rc3, and Rd3is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; or, any Rc3and Rd3attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group; each Rb3is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Re3is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Rfiand Rg3are independently selected from H, C1-6 alkyl, C1-6 alkoxy, Ci- 6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;

[0204] R5is selected from H and C1-4 alkyl;

[0205] R6is selected from H and C1-4 alkyl;

[0206] R7is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R7are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R7Asubstituents; each R7Ais independently selected from NRc7ARd7A, -NRc7AC(O)Ra7A, - NRc7AC(O)ORa7A, -NRc7AC(O)NRc7ARd7A, -NRc7AS(O)2Rb7A, -NRc7AS(O)2NRc7ARd7A, -NRc7AORa7A, -NRc7AS(O)Rb7A, -NRc7AS(O)NRc7ARd7A, -NRc7AC(=NRe7A)Ra7A, - NRc7AC(=NRe7A)NRc7ARd7A, -NRc7AS(O)(=NRe7A)Rb7A, - NRc7AS(O)(=NRe7A)NRc7ARd7A, and -NRc7AS(O)NRc7AC(O)Rb7A; each Ra7A, Rc7A, and Rd7Ais independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; or, any Rc7Aand Rd7Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group; each Rb7Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Re7Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; and each RGis independently selected from OH, CN, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-Ci-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-3 alkylamino, di(Ci-3 alkyl)amino, thio, C1-3 alkylthio, C1-3 alkylsulfinyl, Ci- 3 alkyl sulfonyl, carbamyl, C1-3 alkylcarbamyl, di(Ci-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxy carbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di (C 1-3 alkyl)aminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(Ci-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di (C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di(Ci-3 alkyl)aminocarbonylamino.

[0207] In some embodiments:

[0208] = is a single or double bond; n is 0, 1, or 2;

[0209] X is C or N;

[0210] Y is C or N;

[0211] Z is O;

[0212] X1is CR5;

[0213] X2is CR6;

[0214] X3is CR7;

[0215] Ring A is phenyl or 5-6 membered heteroaryl;

[0216] R1is selected from C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl, wherein the C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0217] R2is selected from C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each R2Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; each R3is independently selected from halo, C1-6 alkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, (phenyl)-Ci-4 alkyl, and -C(O)NRc3Rd3, wherein the C1-6 alkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, and (phenyl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, or 4 independently selected R3Asubstituents; each Rc3and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R3Ais independently selected from C1-6 alkyl;

[0218] R5is selected from H and C1-4 alkyl;

[0219] R6is selected from H and C1-4 alkyl;

[0220] R7is selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, and 5- 6 membered heteroaryl of R7are each optionally substituted with 1, 2, 3, or 4 independently selected R7Asubstituents; each R7Ais independently selected from C1-6 alkyl, 4-7 membered heterocycloalkyl, -C(O)Ra7A, -C(O)NRc7ARd7A, and NRc7ARd7A; each Ra7A, Rc7A, and Rd7Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl of Rc7Aand Rd7Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; and each RGis independently selected from OH, CN, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-Ci-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-3 alkylamino, di(Ci-3 alkyl)amino, thio, C1-3 alkylthio, C1-3 alkylsulfinyl, Ci- 3 alkyl sulfonyl, carbamyl, C1-3 alkylcarbamyl, di(Ci-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxy carbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di (C 1-3 alkyl)aminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(Ci-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di (C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di(Ci-3 alkyl)aminocarbonylamino.

[0221] In some embodiments:

[0222] = is a single or double bond; n is 0, 1, or 2;

[0223] X is C or N;

[0224] Y is C or N;

[0225] Z is O;

[0226] X1is CR5;

[0227] X2is CR6;

[0228] X3is CR7;

[0229] Ring A is phenyl or 5-6 membered heteroaryl;

[0230] R1is selected from C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl, wherein the C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0231] R2is selected from C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each R2Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; each R3is independently selected from -C(O)NRc3Rd3; each Rc3and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;

[0232] R5is selected from H and Ci-4 alkyl;

[0233] R6is selected from H and Ci-4 alkyl;

[0234] R7is selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of R7are each optionally substituted with 1, 2, 3, or 4 independently selected R7Asubstituents; each R7Ais independently selected from NRc7ARd7A; each RC7Aand Rd7Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, and C3-10 cycloalkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, and C3-10 cycloalkyl of Rc7Aand Rd7Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; and each RGis independently selected from OH, CN, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-Ci-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-3 alkylamino, di(Ci-3 alkyl)amino, thio, C1-3 alkylthio, C1-3 alkylsulfinyl, Ci- 3 alkyl sulfonyl, carbamyl, C1-3 alkylcarbamyl, di(Ci-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxy carbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di (C 1-3 alkyl)aminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(Ci-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di (C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di(Ci-3 alkyl)aminocarbonylamino.

[0235] In some embodiments:

[0236] = is a single or double bond; n is 0, 1, or 2;

[0237] X is C or N;

[0238] Y is C or N;

[0239] Z is O;

[0240] R1is selected from C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl, wherein the C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0241] R2is independently selected from each R3is independently selected from halo, C1-6 alkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, (phenyl)-Ci-4 alkyl, and -C(O)NRc3Rd3, wherein the C1-6 alkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, and (phenyl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, or 4 independently selected R3Asubstituents; each Rc3and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R3Ais independently selected from C1-6 alkyl; R5is selected from H and C1-4 alkyl;

[0242] R6is selected from H and C1-4 alkyl;

[0243] R7is selected from H, fluoro, chloro, bromo, methyl, each RGis independently selected from CN, halo, C1-4 alkyl, C1-4 alkoxy, and di(Ci-3 alkyl)amino.

[0244] In some embodiments the compound of Formula I is a compound of Formula

[0245] II: or a pharmaceutically acceptable salt thereof.

[0246] In some embodiments the compound of Formula I is a compound of Formula

[0247] Ila: or a pharmaceutically acceptable salt thereof.

[0248] In some embodiments the compound of Formula I is a compound of Formula

[0249] III:

[0250] III or a pharmaceutically acceptable salt thereof.

[0251] In some embodiments the compound of Formula I is a compound of Formula

[0252] Illa: or a pharmaceutically acceptable salt thereof.

[0253] In some embodiments the compound of Formula I is a compound of Formula

[0254] IV: or a pharmaceutically acceptable salt thereof.

[0255] In some embodiments the compound of Formula I is a compound of Formula IVa: or a pharmaceutically acceptable salt thereof.

[0256] In some embodiments the compound of Formula I is a compound of Formula

[0257] V or a pharmaceutically acceptable salt thereof.

[0258] In some embodiments the compound of Formula I is a compound of Formula Va: Va or a pharmaceutically acceptable salt thereof.

[0259] In some embodiments the compound of Formula I is a compound of Formula

[0260] VI:

[0261] VI or a pharmaceutically acceptable salt thereof.

[0262] In some embodiments, the compound of Formula I is a compound of Formula

[0263] VII:

[0264] VII or a pharmaceutically acceptable salt thereof.

[0265] In some embodiments, the compound of Formula I is a compound of Formula

[0266] Vila:

[0267] Vila or a pharmaceutically acceptable salt thereof.

[0268] In some embodiments, the compound of Formula I is a compound of Formula

[0269] VIII:

[0270] VIII or a pharmaceutically acceptable salt thereof.

[0271] In some embodiments, the compound of Formula I is a compound of Formula Villa:

[0272] Villa or a pharmaceutically acceptable salt thereof.

[0273] In some embodiments, the compound of Formula I is a compound of Formula IX:

[0274] IX or a pharmaceutically acceptable salt thereof.

[0275] In some embodiments, the compound of Formula I is a compound of Formula IX:

[0276]

[0277] IXa or a pharmaceutically acceptable salt thereof.

[0278] In some embodiments, the compound provided herein is selected from:

[0279] 9-bromo-N-methyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-3- carboxamide;

[0280] 9-bromo-N-(cyclopropylmethyl)-4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N- (l-methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-3- carboxamide;

[0281] N-benzyl-9-bromo-4-((l -methyl- lH-pyrazol-4-yl)methyl)-7-(N-(l - methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-3- carboxamide;

[0282] 9-bromo-3-iodo-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-7-sulfonamide;

[0283] 9-bromo-4-((l -methyl- lH-pyrazol-4-yl)methyl)-N-(l -methylcy cl opropyl)-5- oxo-4, 5 -dihy droimidazof 1 , 5 -a] quinazoline-7-sulfonamide;

[0284] 3-iodo-4-((l -methyl-lH-pyrazol-4-yl)methyl)-N-(l -methylcy cl opropyl)-5- oxo-9-phenyl-4,5-dihydroimidazo[l,5-a]quinazoline-7-sulfonamide;

[0285] 9-((cyclopropyl(methyl)amino)methyl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-7- sulfonamide;

[0286] 9-bromo-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5- oxo-4, 5-dihy droimidazof l,2-a]quinazoline-7-sulfonamide;

[0287] 9-(4-isobutyryl-3-methylpiperazin-l-yl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazoline-7- sulfonamide; N,N,2-trimethyl-4-(4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9- yl)piperazine-l -carboxamide;

[0288] 4-((l-methyl-lH-pyrazol-4-yl)methyl)-9-(3-methyl-4-(morpholine-4- carbonyl)piperazin-l-yl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5- a]quinazoline-7-sulfonamide;

[0289] 9-(4-(l -methoxy cyclopropane- 1 -carbonyl)-3 -methylpiperazin- 1 -yl)-4-(( 1 - methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0290] 9-(4-(2 -fluoro-2-methylpropanoyl)-3-methylpiperazin-l-yl)-4-((l -methyl- 1H- pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5- a]quinazoline-7-sulfonamide;

[0291] 9-(4-(l -cyanocyclopropane- 1 -carbonyl)-3 -methylpiperazin- 1 -yl)-4-(( 1 - methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0292] 9-(4-(3 , 3 -difluorocyclobutane- 1 -carbonyl)-3 -methylpiperazin- 1 -yl)-4-(( 1 - methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0293] 9-(4-(l-methoxycyclopropane-l-carbonyl)-4,7-diazaspiro[2.5]octan-7-yl)-4- ((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0294] 9-(4-(cyclopropanecarbonyl)piperazin-l-yl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazoline-7- sulfonamide;

[0295] N,N-dimethyl-4-(4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9- yl)piperazine-l -carboxamide;

[0296] 4-((l -methyl- lH-pyrazol-4-yl)methyl)-N-(l-methylcy cl opropyl)-5-oxo-9-(2- oxa-7-azaspiro[3.5 ]nonan-7-yl)-4, 5 -dihy dropyrazolof 1 , 5 -a] quinazoline-7- sulfonamide; 9-(4-isobutyryl-3-isopropylpiperazin-l-yl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazoline-7- sulfonamide;

[0297] 2-isopropyl-N,N-dimethyl-4-(4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9- yl)piperazine-l -carboxamide;

[0298] 9-(3 -isopropyl-4-( 1 -meth oxy cyclopropane- 1 -carbonyl)piperazin- 1 -y l)-4-(( 1 - methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0299] 9-(4-isobutyryl-3-(methoxymethyl)piperazin-l-yl)-4-((l-methyl-lH-pyrazol- 4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazoline- 7-sulfonamide;

[0300] 2-(methoxymethyl)-N,N-dimethyl-4-(4-((l -methyl- lH-pyrazol-4-yl)methyl)- 7-(N-(l-methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin- 9-yl)piperazine- 1 -carboxamide;

[0301] 9-(4-(l -methoxy cyclopropane- 1 -carbonyl)-3 -(methoxymethyl)piperazin- 1 -yl)-

[0302] 4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0303] 4-(4-((5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)- N,N-dimethylpiperazine- 1 -carboxamide;

[0304] 4-(4-((5-(tert-butyl)-l,2,4-oxadiazol-3-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)- N,N-dimethylpiperazine- 1 -carboxamide;

[0305] 4-(4-((l-(difluoromethyl)-lH-pyrazol-3-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)- N,N-dimethylpiperazine- 1 -carboxamide;

[0306] N,N-dimethyl-4-(7-(N-(l-methylcyclopropyl)sulfamoyl)-4-((2-methylthiazol-

[0307] 5-yl)methyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)piperazine-l- carboxamide; 4-(4-((3,5-dimethylisoxazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)- N,N-dimethylpiperazine- 1 -carboxamide;

[0308] N,N-dimethyl-4-(7-(N-(l-methylcyclopropyl)sulfamoyl)-4-((3- methylisoxazol-4-yl)methyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9- yl)piperazine-l -carboxamide;

[0309] 9-(4-isobutyrylpiperazin- 1 -y l)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-N-( 1 - methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,2-a]quinazoline-7-sulfonamide;

[0310] 9-(4-(2-fluoro-2-methylpropanoyl)piperazin-l-yl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,2-a]quinazoline-7- sulfonamide;

[0311] 9-(4-isobutyryl-3-methylpiperazin-l-yl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,2-a]quinazoline-7- sulfonamide;

[0312] N,N,2-trimethyl-4-(4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydroimidazo[l,2-a]quinazolin-9- yl)piperazine-l -carboxamide;

[0313] 9-(4-(l -methoxy cyclopropane- 1 -carbonyl)-3 -methylpiperazin- 1 -yl)-4-(( 1 - methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydroimidazo[l,2-a]quinazoline-7-sulfonamide;

[0314] 9-(4-(l -cyanocyclopropane- 1 -carbonyl)-3 -methylpiperazin- 1 -yl)-4-(( 1 - methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydroimidazo[l,2-a]quinazoline-7-sulfonamide;

[0315] 9-(4-(l-fluorocyclopropane-l-carbonyl)-3-methylpiperazin-l-yl)-4-((l- methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydroimidazo[l,2-a]quinazoline-7-sulfonamide;

[0316] 9-(4-(l-(dimethylamino)cyclopropane-l-carbonyl)-3-methylpiperazin-l-yl)-4- ((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydroimidazo[l,2-a]quinazoline-7-sulfonamide;

[0317] 4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-9-(4- morpholinocyclohex-l-en-l-yl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazoline-7- sulfonamide; N,N-dimethyl-4-(4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)-3,6- dihydropyridine- 1 (2H)-carboxamide; l-isobutyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5- oxo-4, 5-dihydroimidazo[l,2-a]quinazoline-7-sulfonamide;

[0318] 1 -(cyclohexylmethyl)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-N-( 1 - methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,2-a]quinazoline-7-sulfonamide; l-benzyl-4-((l -methyl- lH-pyrazol-4-yl)methyl)-N-(l-methylcy cl opropyl)-5- oxo-4, 5-dihydroimidazo[l,2-a]quinazoline-7-sulfonamide;

[0319] 1 -(1 -cyclohexylethyl)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-N-( 1 - methylcyclopropyl)-5-oxo-4,5-dihydro-[l,2,4]triazolo[4,3-a]quinazoline-7- sulfonamide;

[0320] 9-fluoro-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5- oxo-4, 5-dihydro-[l, 2, 4]tri azolof l,5-a]quinazoline-7-sulfonamide;

[0321] 3-methyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-l- (4-methylpiperazin-l-yl)-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinoline-7- sulfonamide;

[0322] 9-chloro-3-m ethyl -4-((l -methyl- lH-pyrazol-4-yl)methyl)-N-(l - methylcyclopropyl)-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinoline-7- sulfonamide;

[0323] 4-(3-ethyl -4-((l -methyl- lH-pyrazol-4-yl)methyl)-7-(N-(l - methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)- N,N,2-trimethylpiperazine- 1 -carboxamide; and

[0324] N,N,2-trimethyl-4-(3-(l-methyl-lH-pyrazol-4-yl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-7-(N-(l-methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5- a]quinazolin-9-yl)piperazine-l -carboxamide; or a pharmaceutically acceptable salt thereof.

[0325] In some embodiments, the compound provided herein is selected from:

[0326] 9-bromo-N-methyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-3- carboxamide; 9-bromo-N-(cyclopropylmethyl)-4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N- (l-methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-3- carboxamide;

[0327] N-benzyl-9-bromo-4-((l -methyl- lH-pyrazol-4-yl)methyl)-7-(N-(l - methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-3- carboxamide;

[0328] 9-bromo-3-iodo-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-7-sulfonamide;

[0329] 9-bromo-4-((l -methyl- lH-pyrazol-4-yl)methyl)-N-(l -methylcy cl opropyl)-5- oxo-4, 5 -dihy droimidazof 1 , 5 -a] quinazoline-7-sulfonamide;

[0330] 3-iodo-4-((l -methyl-lH-pyrazol-4-yl)methyl)-N-(l -methylcy cl opropyl)-5- oxo-9-phenyl-4,5-dihydroimidazo[l,5-a]quinazoline-7-sulfonamide;

[0331] 9-((cyclopropyl(methyl)amino)methyl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-7- sulfonamide;

[0332] 9-bromo-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5- oxo-4, 5-dihy droimidazof l,2-a]quinazoline-7-sulfonamide;

[0333] (R)-9-(4-isobutyryl-3-methylpiperazin-l-yl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazoline-7- sulfonamide;

[0334] (R)-N,N,2-trimethyl-4-(4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9- yl)piperazine-l -carboxamide;

[0335] (R)-4-((l-methyl-lH-pyrazol-4-yl)methyl)-9-(3-methyl-4-(morpholine-4- carbonyl)piperazin-l-yl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5- a]quinazoline-7-sulfonamide;

[0336] (R)-9-(4-( 1 -methoxy cyclopropane- 1 -carbonyl)-3 -methylpiperazin- 1 -yl)-4-(( 1 - methyl- lH-pyrazol-4-yl)methyl)-N-(l -methylcy cl opropyl)-5-oxo-4, 5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0337] (R)-9-(4-(2-fluoro-2-methylpropanoyl)-3 -methylpiperazin- l-yl)-4-((l-m ethyl- lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5- a]quinazoline-7-sulfonamide; (R)-9-(4-( 1 -cyanocyclopropane- 1 -carbonyl)-3 -methylpiperazin- 1 -yl)-4-(( 1 - methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0338] (R)-9-(4-(3,3-difluorocyclobutane-l-carbonyl)-3-methylpiperazin-l-yl)-4-((l- methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0339] 9-(4-(l-methoxycyclopropane-l-carbonyl)-4,7-diazaspiro[2.5]octan-7-yl)-4- ((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0340] 9-(4-(cyclopropanecarbonyl)piperazin-l-yl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazoline-7- sulfonamide;

[0341] N,N-dimethyl-4-(4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9- yl)piperazine-l -carboxamide;

[0342] 4-((l -methyl- lH-pyrazol-4-yl)methyl)-N-(l-methylcy cl opropyl)-5-oxo-9-(2- oxa-7-azaspiro[3.5 ]nonan-7-yl)-4, 5 -dihy dropyrazolof 1 , 5 -a] quinazoline-7- sulfonamide;

[0343] (R)-9-(4-isobutyryl-3-isopropylpiperazin-l-yl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazoline-7- sulfonamide;

[0344] (R)-2-isopropyl-N,N-dimethyl-4-(4-((l-methyl-lH-pyrazol-4-yl)methyl)-7- (N-(l-methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9- yl)piperazine-l -carboxamide;

[0345] (R)-9-(3 -isopropyl-4-( 1 -methoxy cyclopropane- 1 -carbonyl)piperazin- 1 -yl)-4- ((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0346] 9-(4-isobutyryl-3-(methoxymethyl)piperazin-l-yl)-4-((l-methyl-lH-pyrazol- 4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazoline- 7-sulfonamide; 2-(methoxymethyl)-N,N-dimethyl-4-(4-((l -methyl- lH-pyrazol-4-yl)methyl)- 7-(N-(l-methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin- 9-yl)piperazine- 1 -carboxamide;

[0347] 9-(4-(l -methoxy cyclopropane- 1 -carbonyl)-3 -(methoxymethyl)piperazin- 1 -yl)-

[0348] 4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0349] 4-(4-((5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)- N,N-dimethylpiperazine- 1 -carboxamide;

[0350] 4-(4-((5-(tert-butyl)-l,2,4-oxadiazol-3-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)- N,N-dimethylpiperazine- 1 -carboxamide;

[0351] 4-(4-((l-(difluoromethyl)-lH-pyrazol-3-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)- N,N-dimethylpiperazine- 1 -carboxamide;

[0352] N,N-dimethyl-4-(7-(N-(l-methylcyclopropyl)sulfamoyl)-4-((2-methylthiazol-

[0353] 5-yl)methyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)piperazine-l- carboxamide;

[0354] 4-(4-((3,5-dimethylisoxazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)- N,N-dimethylpiperazine- 1 -carboxamide;

[0355] N,N-dimethyl-4-(7-(N-(l-methylcyclopropyl)sulfamoyl)-4-((3- methylisoxazol-4-yl)methyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9- yl)piperazine-l -carboxamide;

[0356] 9-(4-isobutyrylpiperazin- 1 -y l)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-N-( 1 - methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,2-a]quinazoline-7-sulfonamide;

[0357] 9-(4-(2-fluoro-2-methylpropanoyl)piperazin-l-yl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,2-a]quinazoline-7- sulfonamide;

[0358] (R)-9-(4-isobutyryl-3-methylpiperazin-l-yl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,2-a]quinazoline-7- sulfonamide; (R)-N,N,2-trimethyl-4-(4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydroimidazo[l,2-a]quinazolin-9- yl)piperazine-l -carboxamide;

[0359] (R)-9-(4-( 1 -methoxy cyclopropane- 1 -carbonyl)-3 -methylpiperazin- 1 -yl)-4-(( 1 - methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydroimidazo[l,2-a]quinazoline-7-sulfonamide;

[0360] (R)-9-(4-( 1 -cyanocyclopropane- 1 -carbonyl)-3 -methylpiperazin- 1 -yl)-4-(( 1 - methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydroimidazo[l,2-a]quinazoline-7-sulfonamide;

[0361] (R)-9-(4-( 1 -fluorocyclopropane- 1 -carbonyl)-3 -methylpiperazin- 1 -yl)-4-(( 1 - methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydroimidazo[l,2-a]quinazoline-7-sulfonamide;

[0362] (R)-9-(4-(l-(dimethylamino)cyclopropane-l-carbonyl)-3-methylpiperazin-l- yl)-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydroimidazo[l,2-a]quinazoline-7-sulfonamide;

[0363] 4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-9-(4- morpholinocyclohex-l-en-l-yl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazoline-7- sulfonamide;

[0364] N,N-dimethyl-4-(4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)-3,6- dihydropyridine- 1 (2H)-carboxamide; l-isobutyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5- oxo-4, 5-dihydroimidazo[l,2-a]quinazoline-7-sulfonamide;

[0365] 1 -(cyclohexylmethyl)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-N-( 1 - methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,2-a]quinazoline-7-sulfonamide; l-benzyl-4-((l -methyl- lH-pyrazol-4-yl)methyl)-N-(l-methylcy cl opropyl)-5- oxo-4, 5-dihydroimidazo[l,2-a]quinazoline-7-sulfonamide;

[0366] 1 -(1 -cyclohexylethyl)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-N-( 1 - methylcyclopropyl)-5-oxo-4,5-dihydro-[l,2,4]triazolo[4,3-a]quinazoline-7- sulfonamide;

[0367] 9-fluoro-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5- oxo-4, 5-dihydro-[l, 2, 4]tri azolof l,5-a]quinazoline-7-sulfonamide; 3-methyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-l- (4-methylpiperazin-l-yl)-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinoline-7- sulfonamide;

[0368] 9-chloro-3-m ethyl -4-((l -methyl- lH-pyrazol-4-yl)methyl)-N-(l - methylcyclopropyl)-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinoline-7- sulfonamide;

[0369] (R)-4-(3-ethyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)- N,N,2-trimethylpiperazine- 1 -carboxamide; and

[0370] (R)-N,N,2-trimethyl-4-(3-(l-methyl-lH-pyrazol-4-yl)-4-((l-methyl-lH- pyrazol-4-yl)methyl)-7-(N-(l-methylcyclopropyl)sulfamoyl)-5-oxo-4,5- dihydropyrazolof 1 ,5 -a]quinazolin-9-yl)piperazine- 1 -carboxamide; or a pharmaceutically acceptable salt thereof.

[0371] It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0372] At various places in the present specification, divalent linking substituents are described. It is specifically intended that each divalent linking substituent include both the forward and backward forms of the linking substituent. For example, - NR(CR’R”)n- includes both -NR(CR’R”)n- and -(CR’R”)nNR-. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups.

[0373] The term “n-membered” where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6- membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10- membered cycloalkyl group.

[0374] As used herein, the phrase “optionally substituted” means unsubstituted or substituted. The substituents are independently selected, and substitution may be at any chemically accessible position. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency.

[0375] As used herein, the phrase “each ‘variable’ is independently selected from” means substantially the same as wherein “at each occurrence ‘variable’ is selected from.”

[0376] Throughout the definitions, the terms “Cn-m” and “Cm-n” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-3, C1-4, C1-6, and the like.

[0377] As used herein, the term “Cn-m alkyl”, employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-l- butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. The term “Cn-m alkyl” is understood to include deuterated analogs of saturated hydrocarbon groups as defined herein, including but not limited to, groups such as trideuteromethyl (CD3), pentadeuteroethyl (CD2CD3), and the like. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, from 2 to 6 carbon atoms, from 2 to 4 carbon atoms, from 2 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0378] As used herein, “Cn-m alkenyl” refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec- butenyl, and the like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. The term “Cn-m alkenyl” is understood to include deuterated analogs of alkenyl groups as defined herein, including but not limited to, groups such as trideuteroethenyl (-CD=CD2), tetradeuteropropenyl, (-CD=CD-CD2), and the like.

[0379] As used herein, “Cn-m alkynyl” refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-l-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. The term “Cn-m alkynyl” is understood to include deuterated analogs of alkynyl groups as defined herein, including but not limited to, groups such as deuteroethynyl (-C=CD), trideuteropropyn-l-yl, (-OCCD3), and the like.

[0380] As used herein, the term “Cn-m alkoxy”, employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tertbutoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. The term “Cn-m alkoxy” is understood to include deuterated analogs of the alkyl moiety of the alkoxy groups as defined herein, including but not limited to, groups such as trideuteromethoxy (-OCD3), pentadeuteroethoxy (-OCD2CD3), and the like.

[0381] As used herein, “Cn-m haloalkoxy”, employed alone or in combination with other terms, refers to a group of formula -O-(haloalkyl), wherein the haloalkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. An example haloalkoxy group is -OCF3. In some embodiments, the haloalkoxy group is a fluoroalkoxy group. The term “Cn-m haloalkoxy” is understood to include deuterated analogs of the haloalkoxy groups as defined herein.

[0382] As used herein, the term “carbonyl”, employed alone or in combination with other terms, refers to a -C(O)- group.

[0383] As used herein, the term “Cn-m alkylcarbonyl” refers to a group of formula -C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. The term “Cn-malkylcarbonyl” is understood to include deuterated analogs of the alkylcarbonyl groups as defined herein.

[0384] As used herein, the term “Cn-m alkyl sulfonyl” refers to a group of formula -S(O)2-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. The term “Cn-malkyl sulfonyl” is understood to include deuterated analogs of the alkylsulfonyl groups as defined herein.

[0385] As used herein, the term “carboxy” refers to a group of formula -C(O)OH. As used herein, the term “amino” refers to a group of formula -NH2.

[0386] As used herein, the term “Cn-m alkylamino”, employed alone or in combination with other terms, refers to a group of formula -NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, alkyl group has 1 to 6 or 1 to 4 carbon atoms. Example Cn-m alkylamino groups include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the like. The term “Cn-m alkylamino” is understood to include deuterated analogs of the alkylamino groups as defined herein.

[0387] As used herein, the term “di(Cn-m alkyl)amino” refers to a group of formula - N(alkyl)2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. The term “di(Cn-m alkyl)amino” is understood to include deuterated analogs of the di(Cn-m alkyl)amino groups as defined herein.

[0388] As used herein, the term “Cn-m alkoxycarbonyl”, employed alone or in combination with other terms, refers to a group of formula -C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-m alkoxycarbonyl” is understood to include deuterated analogs of the alkoxy carbonyl groups as defined herein.

[0389] As used herein, the term “Cn-m alkylcarbonyl”, employed alone or in combination with other terms, refers to a group of formula -C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-m alkylcarbonyl” is understood to include deuterated analogs of the alkylcarbonyl groups as defined herein.

[0390] As used herein, the term “Cn-m alkylcarbonylamino”, employed alone or in combination with other terms, refers to a group of formula -NHC(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-m alkylcarbonylamino” is understood to include deuterated analogs of the alkylcarbonylamino groups as defined herein.

[0391] As used herein, the term “carbamyl”, employed alone or in combination with other terms, refers to a group of formula -C(0)-NH2. As used herein, the term “Cn-m alkylcarbamyl”, employed alone or in combination with other terms, refers to a group of formula -C(O)-NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-m alkylcarbamyl” is understood to include deuterated analogs of the alkylcarbamyl groups as defined herein.

[0392] As used herein, the term “di-Cn-m alkylcarbamyl”, employed alone or in combination with other terms, refers to a group of formula -C(O)-N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, the alkyl group independently has 1 to 6 or 1 to 4 carbon atoms. The term “di-Cn-m alkylcarbamyl” is understood to include deuterated analogs of the dialkylcarbamyl groups as defined herein.

[0393] As used herein, the term “thio” refers to a group of formula -SH.

[0394] As used herein, the term “Cn-m alkylthio”, employed alone or in combination with other terms, refers to a group of formula -S-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-m alkylthio” is understood to include deuterated analogs of the alkylthio groups as defined herein.

[0395] As used herein, the term “Cn-m alkylsulfinyl”, employed alone or in combination with other terms, refers to a group of formula -S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-m alkylsulfinyl” is understood to include deuterated analogs of the alkylsulfinyl groups as defined herein.

[0396] As used herein, the term “Cn-m alkylsulfonyl”, employed alone or in combination with other terms, refers to a group of formula -S(O)2-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-m alkyl sulfonyl” is understood to include deuterated analogs of the alkylsulfonyl groups as defined herein.

[0397] As used herein, “halosulfanyl” refers to a sulfur group having one or more halogen substituents. Example halosulfanyl groups include pentahalosulfanyl groups such as SFs. As used herein, the term “HO-C1-4 alkyl” refers to a group of formula -C1-4 alkylene-OH. The term “HO-C1-4 alkyl” is understood to include deuterated analogs of the HO-C1-4 alkyl groups as defined herein.

[0398] As used herein, the term “C1-4 alkoxy-Ci-4 alkyl” refers to a group of formula - Ci-4 alkylene-O-(Ci-4 alkyl). The term “C1-4 alkoxy-Ci-4 alkyl” is understood to include deuterated analogs of the Ci-4 alkoxy-Ci-4 alkyl groups as defined herein.

[0399] As used herein, the term “aryl,” employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term “Cn-m aryl” refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, aryl groups have from 5 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. In some embodiments, the aryl is phenyl. The term “aryl” is understood to include deuterated analogs of the aryl groups as defined herein, including but not limited to, groups such as pentadeuterophenyl (z.e., perdeuterophenyl, phenyl -t / j), perdeuteronaphthyl, and the like.

[0400] As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br. In some embodiments, a halo is F or Cl. In some embodiments, a halo is F. In some embodiments, a halo is Cl.

[0401] As used herein, “Cn-m haloalkoxy” refers to a group of formula -O-haloalkyl having n to m carbon atoms. Example haloalkoxy groups include OCF3 and OCHF2. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. The term “Cn-mhaloalkoxy” is understood to include deuterated analogs of the haloalkyl moiety of the haloalkoxy groups as defined herein, including but not limited to, groups such as deuterodifluoromethoxy (-OCDF2), di deuterofluor omethoxy (-OCD2F), and the like.

[0402] As used herein, the term “Cn-m haloalkyl”, employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+l halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Example haloalkyl groups include CF3, C2F5, CHF2, CH2F, CC13, CHC12, C2C15and the like. The term “Cn-m haloalkyl” is understood to include deuterated analogs of the haloalkyl groups as defined herein, including but not limited to, groups such as deuterodifluoromethyl (-CDF2), dideuterofluoromethyl (-CD2F), and the like.

[0403] As used herein, “hydroxyl” or “hydroxy” refer to a group of formula -OH.

[0404] As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2 fused rings) groups, spirocycles, and bridged rings (e.g., a bridged bicycloalkyl group). Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido (e.g., C(O) or C(S)). Also included in the definition of cycloalkyl are moi eties that have one or more aromatic rings fused (z.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ringforming atom of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (z.e., C3-10). In some embodiments, the cycloalkyl is a C3-10 monocyclic or bicyclic cycloalkyl. In some embodiments, the cycloalkyl is a C3-7 monocyclic cycloalkyl. In some embodiments, the cycloalkyl is a C4-7 monocyclic cycloalkyl. In some embodiments, the cycloalkyl is a C4-10 spirocycle or bridged cycloalkyl (e.g., a bridged bicycloalkyl group). Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcamyl, cubane, adamantane, bicyclo[l.l. l]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The term “cycloalkyl” is understood to include deuterated analogs of the cycloalkyl groups as defined herein, including but not limited to, groups such as perdeuterocyclopropyl, perdeuterocyclobutyl, perdeuterocyclopentyl, perdeuterocyclohexyl, and the like.

[0405] As used herein, “heteroaryl” refers to a monocyclic or polycyclic (e.g., having 2 fused rings) aromatic heterocycle having at least one heteroatom ring member selected from N, O, S and B. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S and B. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5-, 7-, 8-, 9-, or 10-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl is a 5-, 7-, 8-, 9-, or 10-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl is a 5-6 membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5 membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5 membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl group contains 5 to 10, 5 to 7, 3 to 7, or 5 to 6 ringforming atoms. In some embodiments, the heteroaryl group has 1 to 4 ring-forming heteroatoms, 1 to 3 ring-forming heteroatoms, 1 to 2 ring-forming heteroatoms or 1 ring-forming heteroatom. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. Example heteroaryl groups include, but are not limited to, thienyl (or thiophenyl), furyl (or furanyl), pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4- thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl and l,2-dihydro-l,2-azaborine, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, azolyl, triazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazofl, 2-b]thiazolyl, purinyl, triazinyl, thieno[3,2- b]pyridinyl, imidazofl, 2-a]pyridinyl, 1,5-naphthyridinyl, lH-pyrazolo[4,3- b]pyridinyl, triazolo[4,3-a]pyridinyl, lH-pyrrolo[3,2-b]pyridinyl, lH-pyrrolo[2,3- b]pyridinyl, pyrazolo[l,5-a]pyridinyl, indazolyl, and the like. The term “heteroaryl” is understood to include deuterated analogs of the heteroaryl groups as defined herein, including but not limited to, groups such as perdeuteropyridinyl, perdeuteropyrazinyl, perdeuteropyrimidinyl, and the like.

[0406] As used herein, “heterocycloalkyl” refers to monocyclic or polycyclic heterocycles having at least one non-aromatic ring (saturated or partially unsaturated ring), wherein one or more of the ring-forming carbon atoms of the heterocycloalkyl is replaced by a heteroatom selected from N, O, S, and B, and wherein the ringforming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by one or more oxo or sulfido (e.g., C(O), S(O), C(S), or S(O)2, etc.). When a ring-forming carbon atom or heteroatom of a heterocycloalkyl group is optionally substituted by one or more oxo or sulfide, the O or S of said group is in addition to the number of ring-forming atoms specified herein (e.g., a l-methyl-6- oxo-l,6-dihydropyridazin-3-yl is a 6-membered heterocycloalkyl group, wherein a ring-forming carbon atom is substituted with an oxo group, and wherein the 6- membered heterocycloalkyl group is further substituted with a methyl group). Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having 2 fused rings) systems. Included in heterocycloalkyl are monocyclic and polycyclic 3 to 10, 4 to 10, 5 to 10, 4 to 7, 5 to 7, or 5 to 6 membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles and bridged rings (e.g., a 5 to 10 membered bridged biheterocycloalkyl ring having one or more of the ring-forming carbon atoms replaced by a heteroatom independently selected from N, O, S, and B). The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. The term “heterocycloalkyl” is understood to include deuterated analogs of the heterocycloalkyl groups as defined herein, including but not limited to, groups such as perdeuteroazetidinyl, perdeuteropyrrolidinyl, perdeuteropiperidinyl, and the like.

[0407] Also included in the definition of heterocycloalkyl are moi eties that have one or more aromatic rings fused (i.e., having a bond in common with) to the non- aromatic heterocyclic ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.

[0408] In some embodiments, the heterocycloalkyl group contains 3 to 10 ringforming atoms, 4 to 10 ring-forming atoms, 4 to 8 ring-forming atoms, 3 to 7 ringforming atoms, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1 heteroatom. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O, S and B and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 5-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, and B and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 5 to 10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic 5 to 6 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and having one or more oxidized ring members.

[0409] Example heterocycloalkyl groups include pyrrolidin-2-one (or 2- oxopyrrolidinyl), l,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, 1, 2,3,4- tetrahydroisoquinoline, tetrahydrothiopheneyl, tetrahydrothiopheneyl 1,1 -di oxide, benzazapene, azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl, oxobicyclo[2.1.1]hexanyl, azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1. l]heptanyl, diazabicyclo[3.1. l]heptanyl, azabicyclo[3.2. l]octanyl, diazabicyclo[3.2.1]octanyl, oxobicyclo[2.2.2]octanyl, azabicyclo[2.2.2]octanyl, azaadamantanyl, diazaadamantanyl, oxo-adamantanyl, azaspiro[3.3]heptanyl, 2- azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl, azaspiro[3.5]nonanyl, 7- azaspiro[3.5]nonanyl, oxo-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, diazaspiro[3 ,4]octanyl, oxo-azaspiro[3 ,4]octanyl, azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl, azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxo- azaspiro[4.4]nonanyl, azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl, oxo-diazaspiro[4.4]nonanyl, oxo-dihydropyridazinyl, oxo- 2,6-diazaspiro[3.4]octanyl, oxohexahydropyrrolo[l,2-a]pyrazinyl, 3-oxopiperazinyl, oxo-pyrrolidinyl, oxo-pyridinyl, and the like.

[0410] As used herein, “Co-Pcycloalkyl-Cn-m alkyl-” refers to a group of formula cycloalkyl-alkylene-, wherein the cycloalkyl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms. The term “Co-Pcycloalkyl-Cn-m alkyl-” is understood to include deuterated analogs of the cycloalkyl and / or alkyl moieties of the Co-Pcycloalkyl-Cn-m alkyl- groups as defined herein.

[0411] As used herein “C0.paryl-Cn-m alkyl-” refers to a group of formula arylalkylene-, wherein the aryl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms. The term “Co-Paryl-Cn-m alkyl-” is understood to include deuterated analogs of the aryl and / or alkyl moieties of the Co-Paryl-Cn-m alkyl- groups as defined herein.

[0412] As used herein, “heteroaryl-Cn-m alkyl-” refers to a group of formula heteroaryl-alkylene-, wherein alkylene linking group has n to m carbon atoms. The term “heteroaryl-Cn-m alkyl-” is understood to include deuterated analogs of the heteroaryl and / or alkyl moieties of the heteroaryl-Cn-m alkyl- groups as defined herein.

[0413] As used herein “heterocycloalkyl -Cn-m alkyl-” refers to a group of formula heterocycloalkyl-alkylene-, wherein alkylene linking group has n to m carbon atoms. The term “heterocycloalkyl-Cn-m alkyl-” is understood to include deuterated analogs of the heterocycloalkyl and / or alkyl moieties of the heterocycloalkyl -Cn-m alkylgroups as defined herein.

[0414] As used herein, an “alkyl linking group” or “alkylene linking group” is a bivalent straight chain or branched alkyl linking group (“alkylene group”). For example, “Co-Pcycloalkyl-Cn-m alkyl-”, “Co-Paryl-Cn-m alkyl-”, “phenyl-Cn-m alkyl-”, “heteroaryl-Cn-m alkyl-”, and “heterocycloalkyl -Cn-m alkyl-” contain alkyl linking groups. Examples of “alkyl linking groups” or “alkylene groups” include methylene, ethan- 1,1 -diyl, ethan-l,2-diyl, propan-1, 3-dilyl, propan- 1,2-diyl, propan- 1,1 -diyl and the like. The terms “alkyl linking group” and “alkylene linking group” are understood to include deuterated analogs of the alkylene groups as defined herein. As used herein, a “haloalkyl linking group” or “haloalkylene linking group” is a bivalent straight chain or branched haloalkyl linking group (“haloalkylene group”). Example haloalkylene groups include -CF2-, -C2F4-, -CHF-, -CCI2-, -CHC1-, -C2CI4-, and the like. The terms “haloalkyl linking group” and “haloalkylene linking group” are understood to include deuterated analogs of the haloalkylene groups as defined herein.

[0415] As used herein, a “cycloalkyl linking group” or “cycloalkylene linking group” is a bivalent straight chain or branched cycloalkyl linking group (“cycloalkylene group”). Examples of “cycloalkyl linking groups” or “cycloalkylene groups” include cyclopropy-l,l,-diyl, cyclopropy-l,2-diyl, cyclobut-l,3,-diyl, cyclopent-1, 3, -diyl, cyclopent- 1,4, -diyl, cyclohex- 1,2, -diyl, cyclohex-1, 3, -diyl, cyclohex- 1,4, -diyl, and the like. The terms “cycloalkyl linking group” and “cycloalkylene linking group” are understood to include deuterated analogs of the cycloalkylene groups as defined herein.

[0416] As used herein, a “heterocycloalkyl linking group” or “heterocycloalkylene linking group” is a bivalent straight chain or branched heterocycloalkyl linking group (“heterocycloalkylene group”). Examples of “heterocycloalkyl linking groups” or “heterocycloalkylene groups” include azetidin-l,2-diyl, azeti din- 1,3 -diyl, pyrrolidin- 1,2-diyl, pyrrolidin- 1,3 -diyl, pyrrolidin-2,3-diyl, piperidin-l,2-diyl, piperidin-l,3-diyl, piperidin-l,4-diyl, piperi din-2, 3 -diyl, piperi din-2, 4-diyl, and the like. The terms “heterocycloalkyl linking group” and “heterocycloalkylene linking group” are understood to include deuterated analogs of the heterocycloalkylene groups as defined herein.

[0417] As used herein, a “heteroaryl linking group” or “heteroarylene linking group” is a bivalent straight chain or branched heteroaryl linking group (“heteroarylene group”). Examples of “heteroaryl linking groups” or “heteroarylene groups” include pyrazol- 1,3 -diyl, imidazol-l,2,-diyl, pyri din-2, 3 -diyl, pyridin-2, 4-diyl, pyridin-3,4- diyl, and the like. The terms “heteroaryl linking group” and “heteroarylene linking group” are understood to include deuterated analogs of the heteroarylene groups as defined herein.

[0418] At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas a pyridin-3-yl ring is attached at the 3-position.

[0419] As used herein, the term “oxo” refers to an oxygen atom (z.e., =0) as a divalent substituent, forming a carbonyl group when attached to a carbon (e.g., C=0 or C(0)), or attached to a nitrogen or sulfur heteroatom forming a nitroso, sulfinyl, or sulfonyl group.

[0420] As used herein, the term “independently selected from” means that each occurrence of a variable or substituent (e.g., each RG) , are independently selected at each occurrence from the applicable list.

[0421] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compound has the (R)-configuration. In some embodiments, the compound has the (S)-configuration. The Formulas (e.g., Formula I, Formula II, etc.) provided herein include stereoisomers of the compounds.

[0422] Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallizaion using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as P-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- m ethylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0423] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.

[0424] Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, 2-hydroxypyridine and 2-pyridone, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

[0425] All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents e.g. hydrates and solvates) or can be isolated.

[0426] In some embodiments, preparation of compounds can involve the addition of acids or bases to affect, for example, catalysis of a desired reaction or formation of salt forms such as acid addition salts.

[0427] In some embodiments, the compounds provided herein, or salts thereof, are substantially isolated. By “substantially isolated” is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compounds provided herein. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds provided herein, or salt thereof. The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0428] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0429] The present application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional non -toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0430] Synthesis

[0431] Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and according to various possible synthetic routes. Example synthetic methods for preparing compounds of the invention are provided in the Schemes below.

[0432] The compound of formula 1-10 can be synthesized, for example, using a process shown in Scheme I. Compound of formula 1-1 can be converted to 1-2 via reacting with chlorosulfonic acid. 1-2 can be converted to 1-4 via reacting with suitable amine 1-3. Treatment of 1-4 with suitable reagent (e.g., POCh) can generate 1-5. Intermediate 1-6 can be prepared via hydrolysis of 1-5 with aqueous NaOH solution. 1-7 can be prepared by alkylation of intermediate 1-6. Condensation of 1-7 with tert-butyl isocyanate can afford 1-8, which can be then deprotected under acidic condition to afford 1-9. Amide coupling reaction of 1-9 can afford compound with formula 1-10.

[0433] Scheme I.

[0434] The compound of formula II-4 can be synthesized, for example, using a process shown in Scheme II. Iodination of II- 1 can afford II-2 with suitable reagent (e.g., 7V-Iodosuccinimide). II-2 can be converted into II-3 via suitable reactions (e.g., transition metal-catalyzed cross-coupling reactions). II-3 can be converted into compound with formula II-4 via under suitable conditions (e.g., transition metal- catalyzed cross-coupling reactions).

[0435] Scheme II. Compounds of formula III-3 can be synthesized, for example, using a process shown in Scheme III. A compound of formula 1-7 can be substituted with III-l to afford III-2. III-2 can be converted into compound of formula III-3 via condensation in presence of acid (e.g., HC1).

[0436] Scheme III.

[0437] Compounds of formula IV-2 can be synthesized, for example, via condensation of 1-7 with suitable reagent IV-1.

[0438] Scheme IV.

[0439] The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.

[0440] Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0441] Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g.,JH or13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0442] The expressions, “ambient temperature,” “room temperature,” and “r.t ”, as used herein, are understood in the art, and refer generally to a temperature, e.g. a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 °C to about 30 °C.

[0443] Methods of Use

[0444] The present disclosure provides uses for compounds and compositions described herein. The compounds described herein can inhibit the activity of poly(ADP -ribose) glycohydrolase (PARG). In some embodiments, provided compounds and compositions are for use in medicine (e.g, as therapy). In some embodiments, provided compounds and compositions are useful in treating a disease, disorder, or condition, wherein an underlying pathology is, wholly or partially, mediated by PARG. In some embodiments, provided compounds and compositions are useful in research as, for example, analytical tools and / or control compounds in biological assays.

[0445] Poly(ADP-ribosyl)ation (PARylation) is a dynamic and tightly controlled post-translational modification that plays important roles in multiple cellular processes, including DNA repair, replication, transcription, and cell death (Kang, M., et al. IntJMolSci, 2022, 23, 9826; Le May, N., et al. Mol Cell, 2012, 48, 785). The regulation of the duration and extent of PARylation involves the balance of adding poly(ADP -ribose) (PAR) chains onto target proteins by poly(ADP-ribose) polymerases (PARPs) and removing PAR chains (dePARylation) by poly(ADP- ribose) glycohydrolases. As the major PAR glycohydrolase, PARG is a monogenic protein with five splicing isoforms identified. The full-length, 976 amino acids isoform is mainly located in nucleus, with a N-terminal regulatory domain, a C- terminal catalytic and PAR-binding macrodomain. The other four shorter isoforms are mainly located in cytosol and mitochondria, the nuclear and cytosolic isoforms are shown to be involved in DNA damage repair. (Harrision, D., et al. Front Mol Biosci. 2020, 7, 191; Min, W et al. Carcinogenesis, 2010, 31, 2058).

[0446] Disruption of PAR homeostasis has been linked to increased DNA damage and cell death (Kang, M., et al. IntJMol Sci, 2022, 23, 9826; Schuhwerk, H., et al. Semin Cell Dev Biol, 2017, 63, 81). Genetic depletion of PARG delays dePARylation of target proteins, causing prolonged DNA replication fork stalling and excessive degradation, leading to accumulation of DNA lesions. In cancer cells with compromised DNA repair machinery, including those with homologous recombination repair deficiency, alteration of PARylation by depletion or inhibition of PARG is synthetic lethal (Fathers, C., et al. Cell Cycle, 2012, 11, 990).

[0447] Depletion of PARG sequesters PAR chains on target proteins, thereby blocking NAD+ recycling and leading to cellular NAD+ depletion, which can cause metabolic collapse and cell death (Berger, N., Radiat Res, 1985, 101, 4; Nie, L., et al. eLife, 2023, 12, RP89303). In IDH-mutant tumor models that are deficient in NAD+ salvage pathway, concurrent alkylator (induces hyper-PARylation) and PARG inhibitor (prevents dePARylation) treatment leads to cellular NAD+ depletion and cell death which can be rescued by supplementation of NAD+ derivatives, confirming the mechanistic basis of cytotoxicity (Nagashima, H., et al. Cancer Discov, 2020, 10, 1672). PARylation is involved in initiation and modulation of multiple DNA repair pathways, including base excision repair (BER) (Beneyton, A., et al. NAR Cancer, 2023, 5, zcad043; Ray Chaudhuri, A., et al., Nat Rev Mol Cell Biol, 2017, 18, 610). Genetic studies showed depletion of BER genes induces prolonged activation of PARylation (Koczor, C. A., et al., Cell Rep, 2021, 37, 109917) and sensitizes cells to PARG inhibition (Nie, L., et al., eLife, 2023, 12, RP89303), indicating hyper- PARylation-induced cell death.

[0448] PARP inhibitors are being used to treat cancers clinically, emerging resistance has been reported. Compared to PARP inhibition, targeting PARG prevents dePARylation, providing an alternative therapeutic pathway for disruption of PAR homeostasis. This has been shown to be effective in killing BRC Al -mutant cells that exhibit resistance to PARP inhibition (Chen, S. H., et al. Sci Adv, 2019, 5, eaav4340). PARG inhibition also potentiates the effects of other agents, such as cisplatin, temozolomide, ionizing radiation (Chen, S. H., et al. Sci Adv, 2019, 5, eaav4340; Harrision, D., et al. Front Mol Biosci, 2020, 7, 191), and cell cycle check point inhibitors (Pillay, N., et al., Cancer Cell, 2019, 35, 519), in various cancer models, potentially expand rational applications of PARG inhibition in cancers with lower cellular stress.

[0449] DePARylation is essential in maintaining PAR homeostasis. PARG genedependency data indicate vulnerabilities in cancer cell lines across lineages, including skin, ovary / fallopian tube, lymphoid, lung, CNS / brain, and breast (DepMap, Broad (2023). DepMap 23Q4 Public. Figshare+. Dataset, doi.org / 10.25452 / figshare.plus. 24667905. v2).

[0450] Inhibition or genetic attenuation of PARG selectively kills homologous recombination (HR) protein BRCA1 or BRCA2 deficient cells, indicating the application of PARG inhibitors in BRCA1 / 2 or other HR protein deficient cancers (Fathers et al. Cell Cycle, 2012, 11(5), 990-997; Chen & Yu Sci Adv 2019, 5(4), eaav4340). Synthetic lethality with PARG inhibition has been shown in base excision repair (BER) or replication deficient cells (Nie et al. eLife 2023, 12, RP89303.). These cancers include but are not limited to ovarian, gastric, colorectal, breast, prostate, uterine, pancreatic, lung, melanoma, brain, bladder, head and neck, sarcoma, liver, bile duct, kidney, lymphoma, and leukemia (Starcevic et al. Cell Cycle 2004, 3:8, 996-999; Cerami et al. 2012, 2(5):401-4).

[0451] In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition associated with PARG. In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition, wherein an underlying pathology is, wholly or partially, mediated by PARG. In some embodiments, the compounds provided herein are useful as PARG inhibitors. In some embodiments, the present disclosure provides methods of inhibiting PARG in a subject comprising administering a provided compound or composition. In some embodiments, the present disclosure provides methods of inhibiting PARG in a biological sample comprising contacting the sample with a provided compound or composition.

[0452] In some embodiments, the present disclosure provides methods of treating a disease, disorder or condition associated with PARG in a subject in need thereof, comprising administering to the subject a compound, salt, or composition of the disclosure. In some embodiments, a disease, disorder or condition is associated with mutation of PARG. In some embodiments, the present disclosure provides methods of treating a disease, disorder or condition, wherein an underlying pathology is, wholly or partially, mediated by PARG, in a subject in need thereof, comprising administering to the subject a provided compound or composition.

[0453] In some embodiments, the present disclosure provides methods of treating a variety of PARG-dep endent diseases and disorders.

[0454] In some embodiments, the disease of disorder is a cancer. In some embodiments, the cancer is selected from skin cancer, ovarian cancer, fallopian tube cancer, gastric cancer, colorectal cancer, breast cancer, prostate cancer, uterine cancer, pancreatic cancer, lung cancer, melanoma, brain cancer, bladder cancer, head and neck cancer, sarcoma, liver cancer, bile duct cancer, kidney cancer, lymphoma, and leukemia.

[0455] In some embodiments, the cancer is selected from ovarian cancer, colorectal cancer, breast cancer, prostate cancer, uterine cancer, and pancreatic cancer.

[0456] In some embodiments, the cancer is ovarian cancer.

[0457] In some embodiments, the cancer is colorectal cancer.

[0458] In some embodiments, the cancer is breast cancer.

[0459] In some embodiments, the cancer is prostate cancer.

[0460] In some embodiments, the cancer is uterine cancer.

[0461] In some embodiments, the cancer is pancreatic cancer.

[0462] In some embodiments, provided herein is a method of increasing survival or progression-free survival in a patient, comprising administering a compound provided herein to the patient. In some embodiments, the patient has cancer. In some embodiments, the patient has a disease or disorder described herein. As used herein, progression-free survival refers to the length of time during and after the treatment of a solid tumor that a patient lives with the disease but it does not get worse. Progression-free survival can refer to the length of time from first administering the compound until the earlier of death or progression of the disease. Progression of the disease can be defined by RECIST v. 1.1 (Response Evaluation Criteria in Solid Tumors), as assessed by an independent centralized radiological review committee. In some embodiments, administering of the compound results in a progression free survival that is greater than about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, about 12 months, about 16 months, or about 24 months. In some embodiments, the administering of the compound results in a progression free survival that is at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, or about 12 months; and less than about 24 months, about 16 months, about 12 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, or about 2 months. In some embodiments, the administering of the compound results in an increase of progression free survival that is at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, or about 12 months; and less than about 24 months, about 16 months, about 12 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, or about 2 months.

[0463] The present disclosure further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

[0464] The present disclosure further provides use of a compound described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein.

[0465] As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.

[0466] As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” a PARG with a compound described herein includes the administration of a compound described herein to an individual or patient, such as a human, having a PARG, as well as, for example, introducing a compound described herein into a sample containing a cellular or purified preparation containing the PARG.

[0467] As used herein, the term “individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

[0468] As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent such as an amount of any of the solid forms or salts thereof as disclosed herein that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. An appropriate "effective" amount in any individual case may be determined using techniques known to a person skilled in the art.

[0469] The phrase “pharmaceutically acceptable” is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0470] As used herein, the phrase “pharmaceutically acceptable carrier or excipient” refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients or carriers are generally safe, non-toxic and neither biologically nor otherwise undesirable and include excipients or carriers that are acceptable for veterinary use as well as human pharmaceutical use. In one embodiment, each component is “pharmaceutically acceptable” as defined herein. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

[0471] As used herein, the term “treating” or “treatment” refers to inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology) or ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology) such as decreasing the severity of disease.

[0472] In some embodiments, the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e.g., preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.

[0473] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment (while the embodiments are intended to be combined as if written in multiply dependent form). Conversely, various features of the disclosure which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0474] Combination Therapy

[0475] One or more additional therapeutic agents such as, for example, chemotherapeutics or other anti -cancer agents, anti-inflammatory agents, steroids, immunosuppressants, anesthetics (e.g., for use in combination with a surgical procedure), or other agents useful for treating diseases associated with PARG can be used in combination with the compounds and salts provided herein. The agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

[0476] For example, a combination can include one or more inhibitors of the following kinases for the treatment of cancer: Aktl, Akt2, Akt3, TGF-PR, Pirn, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, CDK4 / 6, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFaR, PDGFpR, CSFIR, KIT, FLK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR / Flt2, Flt4, EphAl, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lek, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf.

[0477] For treating cancer and other proliferative diseases, compounds described herein can be used in combination with targeted therapies, including JAK kinase inhibitors (ruxolitinib, additional JAK1 / 2 and JAK 1 -selective, baricitinib or itacitinib), Pirn kinase inhibitors (e.g., LGH447, INCB053914 and SGI-1776), PI3 kinase inhibitors including PI3K-delta selective and broad spectrum PI3K inhibitors (e.g., parsaclisib and INCB50797), PI3K-gamma inhibitors such as PI3K-gamma selective inhibitors, MEK inhibitors, CSFIR inhibitors (e.g., PLX3397 and LY3022855), TAM receptor tyrosine kinases inhibitors (Tyro-3, Axl, and Mer; e.g., INCB81776), angiogenesis inhibitors, interleukin receptor inhibitors, Cyclin Dependent kinase inhibitors (e.g., palbociclib, riboci clib, and abemaciclib), BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (Bortezomib, Carfilzomib), HD AC -inhibitors (panobinostat, vorinostat), DNA methyl transferase inhibitors, dexamethasone, bromo and extra terminal family members inhibitors (for example, bromodomain inhibitors or BET inhibitors, such as OTX015, CPI-0610, INCB54329 or INCB57643), LSD1 inhibitors (e.g., GSK2979552, INCB59872 and INCB60003), estrogen receptor modulators (e.g., fulvestrant), androgen receptor modulators (e.g., enzalutamide), BCL2 inhibitors (e.g., venetoclax), hypoxia-inducible factor-2 alpha inhibitors (e.g., belzutifan), exportin-1 (XPO-1) inhibitors (e.g., selinexor), KRAS inhibitors (e.g., sotorasib), arginase inhibitors (e.g., INCB1158), indoleamine 2,3- di oxygenase inhibitors (e.g., epacadostat, NLG919 or BMS-986205), PARP inhibitors (e.g., olaparib or rucaparib), and inhibitors of BTK such as ibrutinib. For treating cancer and other proliferative diseases, compounds described herein can be used in combination with chemotherapeutic agents, agonists or antagonists of nuclear receptors, or other anti -proliferative agents. Compounds described herein can also be used in combination with a medical therapy such as surgery or radiotherapy, e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes.

[0478] Examples of suitable chemotherapeutic agents include any of: abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amidox, amsacrine, anastrozole, aphidicolon, arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab, bexarotene, baricitinib, bendamustine, bicalutamide, bleomycin, bortezombi, bortezomib, brivanib, buparlisib, busulfan intravenous, busulfan oral, calusterone, camptosar, capecitabine, carboplatin, carmustine, cediranib, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin, dalteparin sodium, dasatinib, dactinomycin, daunorubicin, decitabine, degarelix, denileukin, denileukin diftitox, deoxycoformycin, dexrazoxane, didox, docetaxel, doxorubicin, droloxafine, dromostanolone propionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin, epothilones, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, idelalisib, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lonafamib, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, navelbene, necitumumab, nelarabine, neratinib, nilotinib, nilutamide, niraparib, nofetumomab, oserelin, oxaliplatin, paclitaxel, pamidronate, panitumumab, panobinostat, pazopanib, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pilaralisib, pipobroman, plicamycin, ponatinib, porfimer, prednisone, procarbazine, quinacrine, ranibizumab, rasburicase, regorafenib, reloxafine, revlimid, rituximab, rucaparib, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, tegafur, temozolomide, teniposide, testolactone, tezacitabine, thalidomide, thioguanine, thiotepa, tipifamib, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, triapine, trimidox, triptorelin, uracil mustard, valrubicin, vandetanib, vinblastine, vincristine, vindesine, vinorelbine, vorinostat, veliparib, talazoparib, and zoledronate.

[0479] Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the “Physicians’ Desk Reference” (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[0480] Example anti-inflammatory agents include, but are not limited to, aspirin, choline salicylates, celecoxib, diclofenac potassium, diclofenac sodium, diclofenac sodium with misoprostol, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, meclofenamate sodium, mefenamic acid, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxican, rofecoxib, salsalate, sodium salicylate, sulindac, tolmetin sodium, and valdecoxib.

[0481] Example steroids include, but are not limited to, corticosteroids such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone.

[0482] Example immunosuppressants include, but are not limited to, azathioprine, chlorambucil, cyclophosphamide, cyclosporine, daclizumab, infliximab, methotrexate, and tacrolimus.

[0483] Example anesthetics include, but are not limited, to local anesthetics (e.g., lidocaine, procain, ropivacaine) and general anesthetics (e.g., desflurane, enflurane, halothane, isoflurane, methoxyflurane, nitrous oxide, sevoflurane, amobarbital, methohexital, thiamylal, thiopental, diazepam, lorazepam, midazolam, etomidate, ketamine, propofol, alfentanil, fentanyl, remifentanil, buprenorphine, butorphanol, hydromorphone levorphanol, meperidine, methadone, morphine, nalbuphine, oxymorphone, pentazocine).

[0484] In some embodiments, the additional therapeutic agent is administered simultaneously with a compound or salt provided herein. In some embodiments, the additional therapeutic agent is administered after administration of the compound or salt provided herein. In some embodiments, the additional therapeutic agent is administered prior to administration of the compound or salt provided herein. In some embodiments, the compound or salt provided herein is administered during a surgical procedure. In some embodiments, the compound or salt provided herein is administered in combination with an additional therapeutic agent during a surgical procedure.

[0485] As provided herein, the additional compounds, inhibitors, agents, etc. can be combined with the compounds provided herein in a single or continuous dosage form, or they can be administered simultaneously or sequentially as separate dosage forms.

[0486] Pharmaceutical Formulations and Dosage Forms

[0487] When employed as pharmaceuticals, the compounds of the invention can be administered in the form of pharmaceutical compositions which refers to a combination of a compound of the invention, or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral. Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0488] This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers. In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10 % by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0489] In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.

[0490] The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0491] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these pre-formulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid pre-formulation is then subdivided into unit dosage forms of the type described above.

[0492] The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.

[0493] The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils.

[0494] The compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.

[0495] The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.

[0496] The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

[0497] The therapeutic dosage of the compounds of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0498] The compositions of the disclosure can further include one or more additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are provided herein.

[0499] Labeled Compounds and Assay Methods

[0500] Another aspect of the present invention relates to fluorescent dye, spin label, heavy metal or radio-labeled compounds of the invention that would be useful not only in imaging but also in assays, both in vitro and in vivo, for localizing and quantitating the PARG in tissue samples, including human, and for identifying PARG by inhibition binding of a labeled compound. Accordingly, the present invention includes PARG cellular assays that contain such labeled compounds.

[0501] The present invention further includes isotopically-labeled compounds of the invention. An “isotopically” or “radio-labeled” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (z.e., naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to2H (also written as D for deuterium),3H (also written as T for tritium),nC,13C,14C,13N,15N,15O,17O,18O,18F,35S,36C1,82Br,75Br,76Br,77Br,123I,124I,125I and131I. The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro FGFR enzyme labeling and competition assays, compounds that incorporate3H,14C,82Br,1251 ,131I, or35S will generally be most useful. For radio-imaging applicationsnC,18F,125I,123I,124I,131I,75Br,76Br or77Br will generally be most useful.

[0502] One or more constituent atoms of the compounds presented herein can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, one or more atoms are replaced or substituted by deuterium. For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced by deuterium atoms (e.g., one or more hydrogen atoms of a Ci-6 alkyl group of Formula I can be optionally substituted with deuterium atoms, such as -CD3 being substituted for -CH3). In some embodiments, alkyl groups of the disclosed Formulas (e.g., the compound of any of Formulas I- VI) can be perdeuterated.

[0503] In some embodiments, the compound provided herein (e.g., the compound of any of Formulas I- VI), or a pharmaceutically acceptable salt thereof, comprises at least one deuterium atom.

[0504] In some embodiments, the compound provided herein (e.g., the compound of any of Formulas I- VI), or a pharmaceutically acceptable salt thereof, comprises two or more deuterium atoms.

[0505] In some embodiments, the compound provided herein (e.g., the compound of any of Formulas I- VI), or a pharmaceutically acceptable salt thereof, comprises three or more deuterium atoms. In some embodiments, for a compound provided herein (e.g., the compound of any of Formulas I- VI), or a pharmaceutically acceptable salt thereof, all of the hydrogen atoms are replaced by deuterium atoms (z.e., the compound is “perdeuterated”).

[0506] It is understood that a “radio-labeled ” or “labeled compound” is a compound that has incorporated at least one radionuclide. In some embodiments the radionuclide is selected from the group consisting of3H,14C,1251 ,35S and82Br.

[0507] Synthetic methods for including isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in various studies such as NMR spectroscopy, metabolism experiments, and / or assays.

[0508] Substitution with heavier isotopes, such as deuterium, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances, (see e.g., A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210; R. Xu et. al. J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular, substitution at one or more metabolism sites may afford one or more of the therapeutic advantages.

[0509] A radio-labeled compound of the invention can be used in a screening assay to identify / evaluate compounds. In general terms, a newly synthesized or identified compound (i.e., test compound) can be evaluated for its ability to reduce binding of the radio-labeled compound of the invention to the PARG. Accordingly, the ability of a test compound to compete with the radio-labeled compound for binding to the PARG directly correlates to its binding affinity.

[0510] Kits

[0511] The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of PARG-associated diseases or disorders referred to herein which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit.

[0512] The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non-critical parameters which can be changed or modified to yield essentially the same results. The compounds of the Examples were found to be inhibitors of P ARG as described below.

[0513] EXAMPLES

[0514] Experimental procedures for compounds of the invention are provided below. Preparatory LC-MS purifications of some of the compounds prepared were performed on Waters mass directed fractionation systems. The basic equipment setup, protocols, and control software for the operation of these systems have been described in detail in the literature. See e.g. “Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K. Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification”, K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated were typically subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity check.

[0515] Some of the compounds prepared were also separated on a preparative scale by reverse-phase high performance liquid chromatography (RP-HPLC) with MS detector or flash chromatography (silica gel) as indicated in the Examples. Example 1. 9-Bromo-N-methyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-3- carboxamide

[0516] Step 1: 8-Bromo-2-hydroxy-4-oxo-3,4-dihydroquinazoline-6-sulfonyl chloride

[0517] 8-Bromo-2-hydroxyquinazolin-4(3H)-one (25 g, 103.7 mmoL) was added portion wise to a stirring chlorosulfonic acid (69 mL) at room temperature (rt). After addition, the mixture was heated to 100 °C for 5h. The mixture was allowed to cool to rt and then added dropwise to stirring ice water. The precipitated solid was filtered and dried to afford the desired product as a light brown solid (29.7 g, 85%).

[0518] Step 2: 8-Bromo-2-hydroxy-N-( 1 -methylcyclopropyl)-4-oxo-3, 4-dihydroquinazoline- 6-sulfonamide

[0519] To a mixture of 8-bromo-2-hydroxy-4-oxo-3,4-dihydroquinazoline-6-sulfonyl chloride (30 g, 88mmol) and 1-methylcyclopropanamine hydrochloride (9.43 g, 132.5 mmol) in DCM (600 mL) was added DIEA (48.9 mL, 265 mmol) dropwise at 0 °C. After addition, the mixture was allowed to warm to rt for Ih. The mixture was stirred at rt for 2h before concentrated and purified using by flash column chromatography, eluting with 0-100% EtOAc in DCM to afford the desired product as a light brown solid (21.3 g, 65%). Step 3: 8-Bromo-2, 4-dichloro-N-( 1 -methylcyclopropyl)quinazoline-6-sulfonamide

[0520] To a mixture of 8-bromo-2-hydroxy-N-(l-methylcyclopropyl)-4-oxo-3,4- dihydroquinazoline-6-sulfonamide (25 g, 66.8 mmol) in POCI3 (94 mL) was added DIEA (24.6 mL, 133 mmol) at 0 °C. The resulting mixture was stirred at 100 °C for 12h. Upon cooling to rt, the mixture was slowly added onto 2000 mL ice. The resulting solid was collected to afford a light brown solid, which was washed with water. The solid was dried under vacuum to afford the desired product as light brown solid (19.9 g, 73%).

[0521] Step 4: 8-Bromo-2-chloro-4-hydroxy-N-( 1 -methylcyclopropyl)quinazoline-6- sulfonamide

[0522] 8-Bromo-2,4-dichloro-N-(l-methylcyclopropyl)quinazoline-6-sulfonamide (19 g, 46 mmoL) was dissolved in THF (600 mL), the mixture was cooled to 0 °C, then 300 mL of NaOH (3.68 g, 92 mmol) solution was added dropwise. The reaction mixture was stirred at 0 °C for 30 min before acidified to pH 5 using IN HC1 solution. The resulting mixture was diluted with water and extracted with DCM / IPA 3 : 1 solvent mixture. The combined organics were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified using by flash column chromatography, eluting with 0-6% MeOH in DCM to afford the desired product as a light brown solid (7.7 g, 42%). LCMS calculated for CnHnBrC ChS (M+H)+m / z = 391.9; found 392.0.

[0523] Step 5: 8-Bromo-2-chloro-3-( 1 -methyl-lH-pyrazol-4-yl)methyl)-N-( I - methylcyclopropyl)-4-oxo-3,4-dihydroquinazoline-6-sulfonamide

[0524] To a mixture of 8-bromo-2-chloro-4-hydroxy-N-(l- methylcyclopropyl)quinazoline-6-sulfonamide (7.7 g, 19.6 mmol) in DME : DMF (4: 1 mixture, 100 mL) was added 4-(bromomethyl)-l-methyl-lH-pyrazole hydrobromide (6 g, 23.5 mmol), LiBr (3.4 g, 39.2 mmol) and K2CO3 (6.78 g, 49 mmol). The resulting mixture was stirred at rt overnight. The resulting mixture was diluted with water and extracted with EtOAc. The combined organics were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified using flash column chromatography, eluting with 0-6% MeOH in DCM to afford the desired product as a light brown solid (4.5 g, 48%). LCMS calculated for CnHisBrCINsChS (M+H)+m / z = 486.0; found 486.1.

[0525] Step 6: tert-Butyl 9-bromo-4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-3- carboxylate

[0526] To a mixture of KOlBu (1.38 g, 12.3 mmol) in dry DMF (30 mL) under nitrogen was added tert-butyl 2-isocy anoacetate (1.39 g, 9.9 mmol) at 0 °C dropwise. The resulting mixture was stirred at 0 °C for 10 min before 8-bromo-2-chloro-3-((l- methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-4-oxo-3,4- dihydroquinazoline-6-sulfonamide (4 g, 8.2 mmol) was added in one portion. The resulting mixture was warmed to rt and stirred for 30 min. After completion, the reaction was poured into 400 mL cold sat. NH4CI solution. The resulting mixture was diluted with water and extracted with EtOAc. The combined organics were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified using flash column chromatography, eluting with 0-100% EtOAc in DCM to afford the desired product as a pale yellow solid (2.4 g, 51%). LCMS calculated for C24H28BrN60sS (M+H)+m / z = 591.1; found 591.1.

[0527] Step 7: 9-Bromo-4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-3- carboxylic acid tert- Butyl 9-bromo-4-((l -methyl- lH-pyrazol-4-yl)methyl)-7-(N-(l - methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-3- carboxylate (2.4 g, 4.18 mmol) was dissolved in TFA (10 mL). The mixture was stirred for 30 min at 50 °C. After completion, TFA was removed under vacuum. EtOAc (5 mL) and hexanes (20 mL) were added to the residue while stirring. After stirring for 10 min, the resulting solid was collected by filtration and washed with hexanes / EtOAc (1 : 1). The solid was dried under vacuum to provide the pure product (1.78 g, 80%). LCMS calculated for C2oH2oBrN605S (M+H)+m / z = 535.0; found 535.1.

[0528] Step 8: 9-Bromo-N-methyl-4-( ( 1 -methyl-lH-pyrazol-4-yl)methyl)-7-(N-( I - methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-3- carboxamide

[0529] To a mixture of 9-bromo-4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-3- carboxylic acid (10 mg, 0.02 mmol) in DMF (0.5 mL) was added HATU (11 mg, 0.03 mmol), methylamine (15 pL, 2M THF solution), and DIEA (10 pL, 0.06 mmol). After stirring for 1 h, the reaction was diluted with MeOH and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C2iH23BrN?O4S (M+H)+m / z = 548.1; found 548.1.

[0530] Examples 2-3.

[0531] Examples 2-3 in Table 1 were prepared similarly to the procedures described for Example 1.

[0532] Table 1.

[0533] Example 4. 9-Bromo-3-iodo-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-7-sulfonamide

[0534] To a mixture of 9-bromo-4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-3- carboxylic acid (Example 1, Step 7, 200 mg, 0.37 mmol) in DMF (2 mL) under nitrogen was added NaHCCL (125 mg, 1.49 mmol) at 0 °C, after stirring for 5 min, N- iodosuccinimide (NIS) (126 mg, 0.56 mmol) was added in one portion. The resulting mixture was warmed to rt and stirred for 2h under vacuum. After completion, the reaction mixture was quenched with sat. Na2S2O3and diluted with water. The resulting solid was collected as a brown solid by filtration which was purified by silica gel column chromatography, eluted with DCM and EtOAc to provide the desired product as a white solid (159 mg, 70%). LCMS calculated for Ci9Hi9BrIN6O3S (M+H)+m / z = 616.9; found 617.0.

[0535] Example 5. 9-Bromo-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-7-sulfonamide

[0536] A mixture of 9-bromo-3-iodo-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-7-sulfonamide (Example 4, 10 mg, 0.02 mmol) and Pd / C (10% on active carbon, 5 mg) in MeOH (0.5 mL) was purged with hydrogen. The reaction mixture was stirred at rt for 2h. After completion, the reaction mixture was filtered and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for CigthoBrNeChS (M+H)+m / z = 491.0; found 491.2.

[0537] Example 6. 3-Iodo-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-5-oxo-9-phenyl-4,5-dihydroimidazo[l,5-a]quinazoline-7- sulfonamide

[0538] A mixture of 9-bromo-3-iodo-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-7-sulfonamide (Example 4, 20 mg, 0.04 mmol), Xphos-PdG2 (3 mg, 0.005 mmol), ISfeCCL (8 mg, 0.08 mmol), and phenylboronic acid (4 mg, 0.02 mmol) in dioxane (0.5 mL) and water (0.1 mL) was heated at 90 °C for 10 min under nitrogen atmosphere. Upon cooling to rt, the mixture was purified by prep-HPLC (column: Sunfire prep Cl 8 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C25H24IN6O3 S (M+H)+m / z = 615.1 ; found 615.1.

[0539] Example 7. 9-((Cyclopropyl(methyl)amino)methyl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline- 7-sulfonamide

[0540] Step 1: 4-( I -Methyl-lH-pyrazol-4-yl)methyl)-N-( I -methylcyclopropyl)-5-oxo-9- vinyl-4, 5-dihydroimidazo [ 1, 5 -a Jquinazoline- 7 -sulfonamide

[0541] A mixture of 9-bromo-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-7-sulfonamide

[0542] (Example 5) (400 mg, 0.81 mmol), PdChfPPhs)? (56 mg, 0.08 mmol), and tributyl(vinyl)stannane (286 mg, 0.9 mmol) in dioxane (5 mL) was heated at 90 °C for 1 h under nitrogen atmosphere. Upon cooling to rt, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM and MeOH (0 to 6%) to provide the desired product as a pale yellow solid (273 mg, 77%). LCMS calculated for C21H23N6O3S (M+H)+m / z = 439.1; found 439.2. Step 2: 9-Formyl-4-( 1 -methyl- lH-pyrazol-4-yl)methyl)-N-( I -methylcyclopropyl) -5- oxo-4, 5-dihydroimidazo [ 1, 5 -a Jquinazoline- 7 -sulfonamide To the solution of 4-((l -methyl- lH-pyrazol-4-yl)methyl)-N-(l - methylcyclopropyl)-5-oxo-9-vinyl-4,5-dihydroimidazo[l,5-a]quinazoline-7- sulfonamide (273 mg, 0.62 mmol) in THF (6 mL) and DCE (5 mL) was added OsCU (4% water solution, 0.1 mL). The mixture was stirred for 10 min before NaICU (526 mg, 2.46 mmol) in water (4 mL) was added. The reaction was stirred for 3h, then diluted with water and extracted with DCM / IPA (3: 1). The combined organics were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0543] Step 3. 9-(Hydroxymethyl)-4-( ( I -methyl- lH-pyrazol-4-yl)methyl)-N-( I - methylcyclopropyl)-5-oxo-4, 5-dihydroimidazo[ 1, 5-a]quinazoline-7 -sulfonamide

[0544] To the solution of 9-formyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-7-sulfonamide (180 mg, 0.4 mmol) in MeOH (1 mL) and DCM (1 mL) was added NaBJLj (24 mg, 0.6 mmol) in one portion at °C. The mixture was stirred for 10 min quenched with drops of NH4CI solution. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM and MeOH (0 to 10%) to provide the desired product as an off white solid (109 mg, 62%). LCMS calculated for C20H23N6O4S (M+H)+m / z = 443.1; found 443.1.

[0545] Step 4: 9-(Bromomethyl)-4-( ( 1 -methyl- lH-pyrazol-4-yl)methyl)-N-( I - methylcyclopropyl)-5-oxo-4, 5-dihydroimidazo[ 1, 5-a]quinazoline-7 -sulfonamide

[0546] To a mixture of 9-(hydroxymethyl)-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N- (l-methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-7-sulfonamide (109 mg, 0.25 mmol) in THF (4 mL) was added PBr3 (31 pL, 0.3 mmol) at 0 °C. The resulting mixture was warmed to rt and stirred for 1 h. The mixture was then quenched with sat. NaHCCh and extracted with DCM / IPA (3: 1). The combined organics were washed with sat. NaCl, and dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used directly in the next step without further purification.

[0547] Step 5: 9-((Cyclopropyl(methyl)amino)methyl)-4-((l-methyl-lH-pyrazol-4-yl)methyl)- N-( 1 -methylcyclopropyl) -5-oxo-4, 5-dihydroimidazo[ 1, 5 -a quinazoline- 7 -sulfonamide

[0548] To a solution of 9-(bromomethyl)-4-((l -methyl- lH-pyrazol-4-yl)methyl)-N- (l-methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-7-sulfonamide (10 mg, 0.02 mmol) in DMF (0.5 mL) was added N-methylcyclopropanamine (5 mg, 0.09 mmol). The mixture was heated to 70 °C for 30 min. Upon cooling to rt, the mixture was purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C24H30N7O3S (M+H)+m / z = 496.2; found 496.2.

[0549] Example 8. 9-Bromo-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,2-a]quinazoline-7-sulfonamide

[0550] Step 1 : 8-Bromo-2-( 2, 2-dimethoxyethyl)amino)-3-( I -methyl- lH-pyrazol-4- yl)methyl)-N-( I -methylcyclopropyl)-4-oxo-3, 4-dihydroquinazoline-6-sulfonamide

[0551] To a mixture of 8-bromo-2-chl oro-3 -((1 -methyl- lH-pyrazol-4-yl)methyl)-N- (l-methylcyclopropyl)-4-oxo-3,4-dihydroquinazoline-6-sulfonamide (50 mg, 0.1 mmol) in DMSO (0.5 mL) was added 2,2-dimethoxyethan-l -amine (10 mg, 0.2 mmol) and DIEA (24 mg, 0.2 mmol) at rt. The resulting mixture was stirred at 50 °C for 2 h. The mixture was diluted with water and extracted with EtOAc. The combined organics were washed with sat. NaCl, and dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM and EtOAc to provide the desired product as a white solid (42 mg, 76%). LCMS calculated for C2iH28BrN60sS (M+H)+m / z = 555.1 ; found 555.1.

[0552] Step 2: 9-Bromo-4-((l -methyl-lH-pyrazol-4-yl)methyl)-N-(l -methylcyclopropyl)-5- oxo-4, 5-dihydroimidazo [ 1,2 -a quinazoline- 7 -sulfonamide

[0553] To a mixture of 8-bromo-2-((2,2-dimethoxyethyl)amino)-3-((l-methyl-lH- pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-4-oxo-3,4-dihydroquinazoline-6- sulfonamide (20 mg, 0.036 mmol) in DMF (0.1 mL) was added cone. HC1 (0.1 mL). The resulting mixture was stirred at 80 °C for 8 h. Upon cooling to rt, the mixture was purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid (42 mg, 76%). LCMS calculated for Ci9H2oBrN603S (M+H)+m / z = 491.0; found 491.1.

[0554] Example 9. (R)-9-(4-Isobutyryl-3-methylpiperazin-l-yl)-4-((l-methyl-lH- pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5- a] quinazoline-7-sulfonamide

[0555] Step 1 : 5-bromo-6-fluoro-3-[ ( I -methylcyclopropyl) sulfamoyl ]cyclohexa-2, 4-diene-l- carboxylic acid

[0556] To a solution of 1-methylcyclopropanamine hydrochloride (2.96 g, 27.54 mmol) in dioxane / FEO (5: 1) was added A,A-diethylethanamine (10.41 mL, 7.60 g, 75.11 mmol) followed by 3-bromo-5-(chlorosulfonyl)-2-fluorobenzoic acid (8.00 g, 25.04 mmol) in portions at rt. The reaction mixture was stirred at rt for 2 h. The reaction was then concentrated and diluted with water and IN NaOH solution which was then extracted with Et2O (2x). The aqueous phase was acidified with 4N HC1 and extracted with EtOAc. The combined organics were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0557] Step 2: tert-butyl 3-(3-bromo-2-jluoro-5-(N-(l- methylcyclopropyl)sulfamoyl)benzamido)-lH-pyrazole-l-carboxylate

[0558] To a solution of 3-bromo-2-fluoro-5-(N-(l- methylcyclopropyl)sulfamoyl)benzoic acid ( 5.40 g, 15.33 mmol) and tert-butyl 3- amino-lH-pyrazole-1 -carboxylate (3.65 g , 19.93 mmol) in THF was added DIPEA (5.22 mL, 3.96 g, 30.67 mmol) and propanephosphonic acid anhydride ( 19.51 g, 30.67 mmol). The reaction solution was heated at 50 °C for 2 h. After cooling to rt, the reaction solution was diluted with EtOAc, and washed with NaHCOs aqueous solution, water, and then brine. The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography using 40% EtOAc in hexanes. LCMS calculated for CigEfaBrFN^sS (M+H)+m / z = 517.05; found 517.1.

[0559] Step 3: 9-bromo-N-( 1 -methylcyclopropyl) -5-oxo-4, 5-dihydropyrazolo[ 1, 5- a Jquinazoline- 7 -sulfonamide

[0560] To a solution of tert-butyl 3-(3-bromo-2-fluoro-5-(N-(l- methylcyclopropyl)sulfamoyl)benzamido)-lH-pyrazole-l-carboxylate (8.00 g, 15.46 mmol) in DCM was added hydrogen chloride (4M dioxane solution, 39 mL, 154.63 mmol). The reaction mixture was stirred at rt for 6 h, then concentrated. The residue was dissolved in DMF and was added K2CO3 (6.41 g, 46.39 mmol), the reaction mixture was then heated at 140 °C for 3 h. After cooled to rt, the solution was diluted with EtOAc, washed with water, IN HC1 solution and brine. The organic phase was dried over MgSC , filtered and concentrated, then purified by flash chromatography using 10% methanol in DCM. LCMS calculated for CwHuBr^ChS (M+H)+m / z = 397.0; found 397.1.

[0561] Step 4: 9-bromo-4-( ( I -methyl-lH-pyrazol-4-yl)methyl)-N-( I -methylcyclopropyl)-5- oxo-4, 5-dihydropyrazolo[ 1, 5 -a quinazoline- 7 -sulfonamide

[0562] I l l

[0563] To a solution of 9-bromo-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide (1100 mg, 2.77 mmol) in DMF was added K2CO3 (765 mg, 5.54 mmol) and LiBr (481 mg, 5.54 mmol), followed with 4- (bromomethyl)-l-methyl-pyrazole hydrobromide (780 mg, 3.05 mmol). The reaction mixture was then stirred at rt for 6 h before diluted with EtOAc, and washed with water, NaHCCh aqueous solution then brine. The combined organic phase was dried over MgSC , filtered and concentrated, then purified by flash chromatography using 90% EtOAc in DCM. LCMS calculated for Ci9H2oBrN603S (M+H)+m / z = 491.0; found 491.1.

[0564] Step 5: 9-bromo-4-( ( 1 -methyl-lH-pyrazol-4-yl)methyl)-N-( I -methylcyclopropyl)-5- oxo-N-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydropyrazolo[l,5-a]quinazoline-7- sulfonamide

[0565] The mixture of 9-bromo-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide (340 mg, 0.69 mmol) in DMF / THF (1 : 1 5 mL) was added sodium hydride (55 mg, 1.38 mmol) at 0 °C. The reaction mixture was stirred for 10 min, then added 2- (chloromethoxy)ethyl-trimethyl-silane (230 mg, 1.38 mmol). The reaction mixture was stirred at 0 °C for 1 h, then quenched with drops of water, diluted with EtOAc, and washed with water, NaHCOs aqueous solution, then brine. The organic phase was dried over MgSO4, filtered and concentrated, then purified by flash chromatography using 40% EtOAc in hexanes. LCMS calculated for C25H34BrNeO4SSi (M+H)+m / z = 621.0; found 621.1.

[0566] Step 6: tert-butyl (R)-2-methyl-4-(4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-5-oxo-4,5- dihydropyrazolo[ 1, 5 -a ]quinazolin-9-yl)piperazine-l -carboxylate

[0567] The mixture of 9-bromo-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-5-oxo-N-((2-(trimethylsilyl)ethoxy)methyl)-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide (240 mg, 0.39 mmol), tert-butyl (2A)-2-methylpiperazine-l -carboxylate (155 mg, 0.77 mmol), Pd2(dba)s (71 mg, 0.08 mmol), BINAP (48 mg, 0.08 mmol) and CS2CO3 (377 mg, 1.16 mmol) in toluene was degassed with N2 and heated at 80 °C overnight. After cooling to rt, the reaction mixture was filtered and concentrated, then purified by flash chromatography using 80% EtOAc in DCM. LCMS calculated for CsslfeNsOeSSi (M+H)+m / z = 741.3; found 741.3.

[0568] Step 7: (R)-4-( I -methyl- lH-pyrazol-4-yl)methyl)-N-( I -methylcyclopropyl) -9 -( 3- methylpiperazin-l-yl)-5-oxo-4, 5-dihydropyrazolo[ 1, 5 -a quinazoline- 7 -sulfonamide

[0569] A mixture of tert-butyl (R)-2-methyl-4-(4-((l-methyl-lH-pyrazol-4- yl)methyl)-7-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5- a]quinazolin-9-yl)piperazine-l -carboxylate (150 mg, 0.20 mmol) and TFA was heated at 50 °C for 2 h, then concentrate to dryness. The residue was dissolved in DCM, washed with NaHCCh aqueous solution, the organic phase was dried over MgSCU, filtered and concentrated, then purified via flash chromatography using 30% MeOH in DCM. LCMS calculated for C24H31N8O3S (M+H)+m / z = 511.2; found 511.2.

[0570] Step 8: (R)-9-(4-isobutyryl-3-methylpiperazin-l-yl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-( 1 -methylcyclopropyl) -5 -oxo-4, 5-dihydropyrazolo[ 1, 5-a]quinazoline- 7- sulfonamide

[0571] To a solution of (R)-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-9-(3-methylpiperazin-l-yl)-5-oxo-4,5-dihydropyrazolo[l,5- a]quinazoline-7-sulfonamide (10 mg, 0.02 mmol) in acetonitrile was added N,N- diethylethanamine (5 uL, 0.04 mmol) and isobutyryl chloride (4 mg, 0.04 mmol). The reaction mixture was stirred at rt for 30 min, then quenched with drops of water, dilute with acetonitrile and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C28H37N8O4S (M+H)+m / z = 581.3; found 581.3. Example 10. (R)-N,N,2-Trimethyl-4-(4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N- (l-methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9- yl)piperazine-l-carboxamide The title compound was prepared using similar procedures as described for

[0572] Example 9, with dimethylcarbamic chloride replacing isobutyryl chloride in Step 8. The final product was purified by prep-HPLC (column: Sunfire prep Cl 8 column, 30*150 mm, 5 pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C27H36N9O4S (M+H)+ m / z = 582.3; found 582.3.

[0573] Example 11. (R)-4-((l-Methyl-lH-pyrazol-4-yl)methyl)-9-(3-methyl-4-

[0574] (morpholine-4-carbonyl)piperazin-l-yl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide

[0575] The title compound was prepared using similar procedures as described for Example 9, with morpholine-4-carbonyl chloride replacing isobutyryl chloride in Step 8. The final product was purified by prep-HPLC (column: Sunfire prep Cl 8 column, 30*150 mm, 5 m; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C29H38N9O5S (M+H)+ m / z = 624.3; found 624.3.

[0576] Example 12. (R)-9-(4-(l-Methoxycyclopropane-l-carbonyl)-3-methylpiperazin-l- yl)-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide

[0577] To a solution of (R)-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-9-(3-methylpiperazin-l-yl)-5-oxo-4,5-dihydropyrazolo[l,5- a]quinazoline-7-sulfonamide (Example 9, step 7) (10 mg, 0.02 mmol) and 1- methoxycyclopropanecarboxylic acid (5 mg, 0.04 mmol) in acetonitrile was added DIPEA (0.01 mL, 0.04 mmol) and propanephosphonic acid anhydride (25 mg, 0.04 mmol). The reaction mixture was heated at 50 °C for 2 h. After cooling to rt the reaction mixture was diluted with acetonitrile and water, purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C29H37N8O5S (M+H)+ m / z = 609.3; found 609.3.

[0578] Examples 13-15.

[0579] The following Examples 13-15 in Table 2 were prepared similarly as described for Example 12, using appropriately substituted starting materials. Table 2.

[0580] Example 16. 9-(4-(l-Methoxycyclopropane-l-carbonyl)-4,7-diazaspiro[2.5]octan-

[0581] 7-yl)-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide

[0582] Step 1: 4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-9-(4, 7- diazaspiro[ 2.5 Joctan- 7-yl) -4, 5-dihydropyrazolo[ 1, 5 -a Jquinazoline- 7 -sulfonamide The title compound was prepared using similar procedures as described for

[0583] Example 9, with tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate replacing tertbutyl (R)-2-m ethylpiperazine- 1 -carboxylate in Step 6. The final product was purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C25H31N8O3S (M+H)+ m / z = 523.2; found 523.2.

[0584] Step 2: 9-(4-(l-methoxycyclopropane-l-carbonyl)-4, 7-diazaspiro[2.5]octan-7-yl)-4- ((1 -methyl- lH-pyrazol-4-yl)methyl)-N-( I -methylcyclopropyl)-5-oxo-4, 5- dihydropyrazolo[ 1, 5 -a quinazoline- 7 -sulfonamide

[0585] To a solution 4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-5-oxo-9-(4,7-diazaspiro[2.5]octan-7-yl)-4,5-dihydropyrazolo[l,5- a]quinazoline-7-sulfonamide (10 mg, 0.02 mmol) and 1- methoxycyclopropanecarboxylic acid (4 mg, 0.04 mmol) in acetonitrile was added DIPEA (0.01 mL, 0.04 mmol) and propanephosphonic acid anhydride (24 mg, 0.04 mmol) , then heated at 50 °C for 2 h. After cooling to rt the reaction mixture was diluted with acetonitrile and water, purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C30H37N8O5S (M+H)+ m / z = 621.3; found 621.3. Examples 17-19.

[0586] The following Examples 17-19 in Table 3 were prepared similarly as described for Example 9, with suitable amine replacing tert-butyl (2R)-2- m ethylpiperazine- 1 -carboxylate in step 6.

[0587] Table 3.

[0588] Example 20. (R)-9-(4-Isobutyryl-3-isopropylpiperazin-l-yl)-4-((l-methyl-lH- pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5- a] quinazoline-7-sulfonamide

[0589] Step 1: (R)-9-(3-isopropylpiperazin-l-yl)-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-( 1 - methylcyclopropyl)-5-oxo-4, 5-dihydropyrazolo[ 1, 5-a]quinazoline-7 -sulfonamide

[0590] The title compound was prepared using similar procedures as described for Example 9, with tert-butyl (R)-2-isopropylpiperazine-l -carboxylate replacing tert- butyl (R)-2-m ethylpiperazine- 1 -carboxylate in Step 6. The crude product was purified via flash chromatography using 30% MeOH in DCM. LCMS calculated for C26H35N8O3S (M+H)+m / z = 539.2; found 539.3.

[0591] Step 2: (R)-9-(4-isobutyryl-3-isopropylpiperazin-l-yl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-( 1 -methylcyclopropyl) -5 -oxo-4, 5-dihydropyrazolo[ 1, 5-a]quinazoline- 7- sulfonamide

[0592] To a solution of (R)-9-(3-isopropylpiperazin-l-yl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazoline-7- sulfonamide (10 mg, 0.02 mmol) in MeCN was added DIPEA (5 uL, 0.04 mmol) and isobutyryl chloride (4 mg, 0.04 mmol) at 0 °C. The reaction mixture was stirred at rt for 30 min, then quenched with drops of water, dilute with acetonitrile and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C30H41N8O4S (M+H)+m / z = 609.3; found 609.3.

[0593] Example 21. (R)-2-Isopropyl-N,N-dimethyl-4-(4-((l-methyl-lH-pyrazol-4- yl)methyl)-7-(N-(l-methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5- a]quinazolin-9-yl)piperazine-l-carboxamide

[0594] The title compound was prepared using similar procedures as described for Example 20, with dimethylcarbamic chloride replacing isobutyryl chloride in Step 2. The final product was purified by prep-HPLC (column: Sunfire prep Cl 8 column, 30*150 mm, 5 m; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C29H40N9O4S (M+H)+ m / z = 610.3; found 610.3.

[0595] Example 22. (R)-9-(3-Isopropyl-4-(l-methoxycyclopropane-l- carbonyl)piperazin-l-yl)-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide

[0596] The title compound was prepared using similar procedures as described for Example 16, with (R)-9-(3-isopropylpiperazin-l-yl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazoline-7- sulfonamide replacing 4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-5-oxo-9-(4,7-diazaspiro[2.5]octan-7-yl)-4,5-dihydropyrazolo[l,5- a]quinazoline-7-sulfonamide in Step 2. The final product was purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C31H41N8O5S (M+H)+ m / z = 637.3; found 637.3.

[0597] Example 23. 9-(4-Isobutyryl-3-(methoxymethyl)piperazin-l-yl)-4-((l-methyl-lH- pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5- a] quinazoline-7-sulfonamide

[0598] The title compound was prepared using similar procedures as described for Example 9, with tert-butyl 2-(methoxymethyl)piperazine-l -carboxylate replacing tertbutyl (2A)-2-m ethylpiperazine- 1 -carboxylate in Step 6. The final product was purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C29H39N8O5S (M+H)+ m / z = 611.3; found 611.3.

[0599] Example 24. 2-(Methoxymethyl)-N,N-dimethyl-4-(4-((l-methyl-lH-pyrazol-4- yl)methyl)-7-(N-(l-methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5- a]quinazolin-9-yl)piperazine-l-carboxamide

[0600] The title compound was prepared using similar procedures as described for Example 9, with tert-butyl 2-(methoxymethyl)piperazine-l -carboxylate replacing tertbutyl (2A)-2-m ethylpiperazine- 1 -carboxylate in Step 6 and dimethylcarbamic chloride replacing isobutyryl chloride in step 8. The final product was purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C28H38N9O5S (M+H)+ m / z = 612.3; found 612.3.

[0601] Example 25. 9-(4-(l-Methoxycyclopropane-l-carbonyl)-3- (methoxymethyl)piperazin-l-yl)-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide

[0602] The title compound was prepared using similar procedures as described for Example 12, with 9-(3-(methoxymethyl)piperazin-l-yl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazoline-7- sulfonamide replacing (R)-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-9-(3-methylpiperazin-l-yl)-5-oxo-4,5-dihydropyrazolo[l,5- a]quinazoline-7-sulfonamide. The final product was purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C30H39N8O6S (M+H)+ m / z = 639.3; found 639.3.

[0603] Example 26. 4-(4-((5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)- N,N-dimethylpiperazine-l-carboxamide

[0604] Step 1: 9-bromo-N-(l-methylcyclopropyl)-5-oxo-N,4-bis((2-

[0605] ( trimethylsilyl)ethoxy)methyl)-4, 5-dihydropyrazolo[ 1, 5 -a quinazoline- 7 -sulfonamide The mixture of 9-bromo-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide (Example 9, step 3) (1.0 g, 2.52 mmol) in DMF / THF (1 : 1 5mL) was added sodium hydride (403 mg, 10.07 mmol) at 0 °C. The reaction mixture was stirred for 10 min, then added 2-(chloromethoxy)ethyl- trimethyl-silane (1679 mg, 10.07 mmol). The reaction mixture was stirred at rt for 3 h, then quenched with drops of water, diluted with EtOAc, and washed with water, NaHCOs aqueous solution, then brine. The organic phase was dried over MgSCh, filtered and concentrated, then purified by flash chromatography using 60% EtOAc in hexanes. LCMS calculated for C26H42BrN4OsSSi2 (M+H)+m / z = 657.2; found 657.2. Step 2: N,N-dimethyl-4-(7-(N-(l-methylcyclopropyl)-N-((2-

[0606] (trimethylsilyl)ethoxy)methyl)sulfamoyl)-5-oxo-4-((2-(trimethylsilyl)ethoxy)methyl)-

[0607] 4, 5-dihydropyrazolo[ 1, 5 -a ]quinazolin-9-yl)piperazine-l -carboxamide The mixture of 9-bromo-N-(l-methylcyclopropyl)-5-oxo-N,4-bis((2- (trimethylsilyl)ethoxy)methyl)-4,5-dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide (600 mg, 0.91 mmol), N,N-dimethylpiperazine-l -carboxamide (287 mg, 1.82 mmol), Pd2(dba)s (167 mg, 0.18 mmol), BINAP (114 mg, 0.18 mmol) and Cs2COs (892 mg, 2.74 mmol) in toluene was degassed with N2 and heated at 90 °C overnight. After cooling to rt, the reaction mixture was filtered, the solid was washed with DCM. The filtrate was concentrated, then purified by flash chromatography using 70% EtOAc in DCM. LCMS calculated for C33H56N7O6SSi2 (M+H)+m / z = 734.4; found 734.4.

[0608] Step 3: N,N-dimethyl-4-(7-(N-(l-methylcyclopropyl)sulfamoyl)-5-oxo-4,5- dihydropyrazolo[ 1, 5 -a ]quinazolin-9-yl)piperazine-l -carboxamide

[0609] The mixture of N,N-dimethyl-4-(7-(N-(l-methylcyclopropyl)-N-((2- (trimethylsilyl)ethoxy)methyl)sulfamoyl)-5-oxo-4-((2-(trimethylsilyl)ethoxy)methyl)- 4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)piperazine-l-carboxamide (210 mg, 0.29 mmol) in TFA was heated at 50 °C for 2h. After cooling to rt, the reaction mixture was concentrated, then purified by flash chromatography using 70% EtOAc in DCM. LCMS calculated for C21H28N7O4S (M+H)+m / z = 474.2; found 474.2.

[0610] Step 3: 4-(4-((5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)-

[0611] N, N-dimethylpiper azine- 1 -carboxamide

[0612] To a solution of N,N-dimethyl-4-(7-(N-(l-methylcyclopropyl)sulfamoyl)-5- oxo-4, 5 -dihy dropyrazolof 1 , 5 -a] quinazolin-9-yl)piperazine- 1 -carboxamide (10 mg,

[0613] O.02 mmol) in DMF was added K2CO3 (6 mg, 0.04 mmol) and LiBr (4 mg, 0.04 mmol), followed with 2-(chloromethyl)-5-(difluoromethyl)-l,3,4-thiadiazole (8 mg, 0.04 mmol). The reaction mixture was then stirred at rt overnight. The reaction mixture was diluted with ACN and purified by prep-HPLC (column: Sunfire prep Cl 8 column, 30*150 mm, 5 pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C25H30F2N9O4S2 (M+H)+ m / z = 622.2; found 622.2.

[0614] Examples 27-31.

[0615] The following Examples 27-31 in Table 4 were prepared similarly as described for Example 26, using appropriately substituted starting materials.

[0616] Table 4.

[0617] Example 32. 9-(4-Isobutyrylpiperazin-l-yl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,2-a]quinazoline- 7-sulfonamide

[0618] Step 1: 8-bromo-2-((2,2-dimethoxyethyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-3- ((1 -methyl- lH-pyrazol-4-yl)methyl)-N-( I -methylcyclopropyl)-4-oxo-N-( (2- (trimethylsilyl)ethoxy)methyl)-3,4-dihydroquinazoline-6-sulfonamide

[0619] The mixture of 8-bromo-2-((2,2-dimethoxyethyl)amino)-3-((l-methyl-lH- pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-4-oxo-3,4-dihydroquinazoline-6- sulfonamide (Example 8, step 1) (260 mg, 0.47 mmol) in DMF (2 mL) was added sodium hydride (56 mg, 1.4 mmol) at 0 °C. The reaction mixture was stirred for 10 min, then added 2-(chloromethoxy)ethyl-trimethyl-silane (234 mg, 1.4 mmol). The reaction mixture was stirred at rt for 1 h, then quenched with drops of water, diluted with EtOAc, and washed with water, and brine. The organic phase was dried over MgSO4, filtered and concentrated, then purified by flash chromatography using 60% EtOAc in hexanes. LCMS calculated for CssHseBrNeOySSi? (M+H)+m / z = 815.2; found 815.3.

[0620] Step 2: tert-butyl 4-(2-((2,2-dimethoxyethyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-

[0621] 3-( I -methyl-lH-pyrazol-4-yl)methyl)-6-(N-( I -methylcyclopropyl)-N-( (2- (trimethylsilyl)ethoxy)methyl)sulfamoyl)-4-oxo-3,4-dihydroquinazolin-8- yl)piperazine-l -carboxylate

[0622] The mixture of 8-bromo-2-((2,2-dimethoxyethyl)((2- (trimethylsilyl)ethoxy)methyl)amino)-3-((l -methyl- lH-pyrazol-4-yl)methyl)-N-(l - methylcyclopropyl)-4-oxo-N-((2-(trimethylsilyl)ethoxy)methyl)-3,4- dihydroquinazoline-6-sulfonamide (80 mg, 0.12 mmol), tert-butyl piperazine-1- carboxylate (37 mg, 0.23 mmol), Pd2(dba)s (8 mg, 0.01 mmol), BINAP (5 mg, 0.01 mmol) and CS2CO3 (41 mg, 0.13 mmol) in toluene was degassed with N2 and heated at 80 °C overnight. After cooling to rt, the reaction mixture was filtered, the solid was washed with DCM. The filtrate was concentrated, then purified by flash chromatography using 80% EtOAc in DCM. LCMS calculated for C42H73NsO9SSi2 (M+H)+m / z = 921.5; found 921.5.

[0623] Step 3: 4-( ( 1 -methyl- lH-pyrazol-4-yl)methyl)-N-( I -methylcyclopropyl)-5-oxo-9- (piperazin-l-yl) -4, 5-dihydroimidazo[ 1, 2 -a quinazoline- 7 -sulfonamide

[0624] The mixture of tert-butyl 4-(2-((2,2-dimethoxyethyl)((2- (trimethylsilyl)ethoxy)methyl)amino)-3-((l -methyl- lH-pyrazol-4-yl)methyl)-6-(N-(l - methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-4-oxo-3,4- dihydroquinazolin-8-yl)piperazine-l -carboxylate (40 mg, 0.04 mmol) in DMF (0.2 mL) was added cone. HC1 (0.2 mL) at 0 °C. The reaction mixture was then heated at 110 °C for 10 min. After cooling to rt, the reaction mixture was diluted with methanol and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C23H29N8O3S (M+H)+ m / z = 497.2; found 497.2.

[0625] Step 4: 9-( 4-isobutyrylpiperazin-l-yl)-4-( I -methyl- lH-pyrazol-4-yl)methyl)-N-( I - methylcyclopropyl)-5-oxo-4, 5-dihydroimidazo[ 1, 2-a]quinazoline-7 -sulfonamide

[0626] To a solution of 4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-5-oxo-9-(piperazin-l-yl)-4,5-dihydroimidazo[l,2-a]quinazoline- 7-sulfonamide (10 mg, 0.02 mmol) in acetonitrile was added A,A-diethylethanamine (5 uL, 0.04 mmol) and isobutyryl chloride (4 mg, 0.04 mmol). The reaction mixture was stirred at rt for 30 min, then diluted with MeOH and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C27H35N8O4S (M+H)+m / z = 567.2; found 567.2.

[0627] Example 33. 9-(4-(2-Fluoro-2-methylpropanoyl)piperazin-l-yl)-4-((l-methyl-lH- pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,2- a] quinazoline-7-sulfonamide

[0628] To a solution 4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-5-oxo-9-(piperazin-l-yl)-4,5-dihydroimidazo[l,2-a]quinazoline- 7-sulfonamide (Example 32) (10 mg, 0.02 mmol) and 2-fluoro-2 -methylpropanoic acid (4 mg, 0.04 mmol) in DMF was added DIPEA (0.01 mL, 0.04 mmol) and HATU (15 mg, 0.04 mmol). The reaction mixture was stirred at rt for 1 h then diluted with methanol, purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C27H34FN8O4S (M+H)+ m / z = 585.2; found 585.2.

[0629] Example 34. (R)-9-(4-Isobutyryl-3-methylpiperazin-l-yl)-4-((l-methyl-lH- pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,2- a] quinazoline-7-sulfonamide

[0630]

[0631] Step 1: (R)-4-( 1 -methyl- lH-pyrazol-4-yl)methyl)-N-( I -methylcyclopropyl) -9 -( 3- methylpiperazin-l-yl)-5-oxo-4, 5-dihydroimidazo [ 1, 2 -a quinazoline- 7 -sulfonamide

[0632] The title compound was prepared using similar procedures as described for Example 32, with tert-butyl (R)-2-m ethylpiperazine- 1 -carboxylate replacing tert-butyl piperazine- 1 -carboxylate in step 2. The crude product was purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C24H31N8O3S (M+H)+ m / z = 511.2; found 511.2.

[0633] Step 2: (R)-9-(4-isobutyryl-3-methylpiperazin-l-yl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-( I -methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[ 1, 2-a]quinazoline-7- sulfonamide

[0634] To a solution of (R)-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-9-(3-methylpiperazin-l-yl)-5-oxo-4,5-dihydroimidazo[l,2- a]quinazoline-7-sulfonamide (10 mg, 0.02 mmol) in acetonitrile was added N,N- diethylethanamine (5 uL, 0.04 mmol) and isobutyryl chloride (4 mg, 0.04 mmol). The reaction mixture was stirred at rt for 30 min, then quenched with drops of water, dilute with acetonitrile and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C28H37N8O4S (M+H)+m / z = 581.3; found 581.3.

[0635] Example 35. (R)-N,N,2-Trimethyl-4-(4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N- (l-methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydroimidazo[l,2-a]quinazolin-9- yl)piperazine-l-carboxamide

[0636] The title compound was prepared using similar procedures as described for Example 34, with dimethylcarbamic chloride replacing isobutyryl chloride in Step 2. The final product was purified by prep-HPLC (column: Sunfire prep Cl 8 column, 30*150 mm, 5 pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C27H36N9O4S (M+H)+ m / z = 582.3; found 582.3.

[0637] Example 36. (R)-9-(4-(l-Methoxycyclopropane-l-carbonyl)-3-methylpiperazin-l- yl)-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydroimidazo[l,2-a]quinazoline-7-sulfonamide To a solution of (R)-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-9-(3-methylpiperazin-l-yl)-5-oxo-4,5-dihydroimidazo[l,2- a]quinazoline-7-sulfonamide (Example 34, step 1) (10 mg, 0.02 mmol) and 1- methoxycyclopropanecarboxylic acid (5 mg, 0.04 mmol) in DMF was added DIPEA (0.01 mL, 0.04 mmol) and HATU (15 mg, 0.04 mmol). The reaction mixture was stirred for 1 h then diluted with methanol, and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C29H37N8O5S (M+H)+ m / z = 609.3; found 609.3.

[0638] Examples 37-39.

[0639] The following Examples 37-39 in Table 5 were prepared similarly as described for Example 36, using appropriately substituted starting materials. Table 5.

[0640] Example 40. 4-((l-Methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-9- (4-morpholinocyclohex-l-en-l-yl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazoline- 7-sulfonamide

[0641] The mixture of 9-bromo-A-(l-methylcyclopropyl)-4-[(l-methylpyrazol-4- yl)methyl]-5-oxo-pyrazolo[l,5-a]quinazoline-7-sulfonamide (Example 9, step 4) (20 mg, 0.04 mmol), 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l- yl)morpholine (21 mg, 0.12 mmol), Pd(dppf)C12 (7 mg, 0.01 mmol) and ISfeCCh (13 mg, 0.12 mmol) in dioxane / FEO (5:1) was degassed with N2, then heated at 80 °C overnight. After cooling to rt the reaction mixture was concentrated, then diluted with acetonitrile and water, and purified by prep-HPLC (column: Sunfire prep Cl 8 column, 30*150 mm, 5 pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C29H36N7O4S (M+H)+ m / z = 578.2; found 578.3. Example 41. N,N-Dimethyl-4-(4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)- 3,6-dihydropyridine-l(2H)-carboxamide

[0642] Step 1: 4-( ( 1 -methyl-lH-pyrazol-4-yl)methyl)-N-( 1 -methylcyclopropyl)-5-oxo-9- ( 1, 2, 3, 6-tetrahydropyridin-4-yl)-4, 5-dihydropyrazolo [ 1, 5-a]quinazoline- 7- sulfonamide

[0643] The mixture of 9-bromo-A-(l-methylcyclopropyl)-4-[(l-methylpyrazol-4- yl)methyl]-5-oxo-pyrazolo[l,5-a]quinazoline-7-sulfonamide (Example 9, step 4) (20 mg, 0.04 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-l(2H)-carboxylate (37 mg, 0.12 mmol), Pd(dppf)C12 (7 mg, 0.01 mmol) and Na2COs (13 mg, 0.12 mmol) in dioxane / FEO (5:1) was degassed with N2, then heated at 80 °C overnight. After cooling to rt the reaction mixture was concentrated and dissolved in TFA. After stirred for 30 min, the reaction mixture was diluted with MeOH and purified by prep-HPLC (column: Sunfire prep Cl 8 column, 30*150 mm, 5 pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C24H28N7O3S (M+H)+ m / z = 494.2; found 494.2. Step 2: N,N-dimethyl-4-( 4-( 1 -methyl-lH-pyrazol-4-yl)methyl)- 7-(N-( 1 - methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)-3,6- dihydropyridine-l(2H)-carboxamide

[0644] To a solution of 4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-5-oxo-9-(l,2,3,6-tetrahydropyridin-4-yl)-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide (10 mg, 0.02 mmol) in DCM was added A,A-diethylethanamine (5 uL, 0.04 mmol) and dimethylcarbamic chloride (4 mg, 0.04 mmol). The reaction mixture was stirred at rt for 30 min, then diluted with MeOH and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C27H33N8O4S (M+H)+m / z = 565.2; found 565.2.

[0645] Example 42. l-Isobutyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,2-a]quinazoline-7-sulfonamide

[0646] Step 1: 2-chloro-3-( 1 -methyl- lH-pyrazol-4-yl)methyl)-N-( I -methylcyclopropyl)-4- oxo-3, 4-dihydroquinazoline-6-sulfonamide

[0647] The title compound was prepared using similar procedures as described for Example 1, with quinazoline-2,4(lH,3H)-dione replacing 8-bromo-2- hydroxyquinazolin-4(3H)-one in Step 1. LCMS calculated for C17H19CIN5O3S (M+H)+m / z = 408.1 ; found 408.1. Step 2: l-isobutyl-4-( ( 1 -methyl- lH-pyrazol-4-yl)methyl)-N-( I -methylcyclopropyl)-5- oxo-4, 5-dihydroimidazo [ 1, 2 -a quinazoline- 7 -sulfonamide

[0648] To a mixture of 2-chloro-3-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-4-oxo-3,4-dihydroquinazoline-6-sulfonamide (30 mg, 0.07 mmol) in DMSO (0.5 mL) was added 1 -amino-4-methylpentan-2-one (20 mg, 0.2 mmol) and DIEA (24 mg, 0.2 mmol) at rt. The resulting mixture was stirred at 50 °C for 2 h. The mixture was diluted with water and extracted with EtOAc. The combined organics were washed with sat. NaCl, and dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in DMF (0.2 mL) and cone. HC1 (0.2 mL), the reaction mixture was stirred at 110 °C for 10 min before diluted with MeOH and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C23H29N6O3S (M+H)+m / z = 469.2; found 469.2.

[0649] Examples 43-44.

[0650] The following Examples 43-44 in Table 6 were prepared similarly as described for Example 42, using appropriately substituted starting materials.

[0651] Table 6.

[0652] Example 45. l-(l-Cyclohexylethyl)-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-5-oxo-4,5-dihydro-[l,2,4]triazolo[4,3-a]quinazoline-7- sulfonamide

[0653] Step 1 : 2-hydrazineyl-3-( 1 -methyl- lH-pyrazol-4-yl)methyl)-N-( I - methylcyclopropyl)-4-oxo-3,4-dihydroquinazoline-6-sulfonamide

[0654] To a solution of 2-chloro-3-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-4-oxo-3,4-dihydroquinazoline-6-sulfonamide (400 mg, 0.82 mmol) in THF (3 mL) was added hydrazine monohydrate (100 uL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was then concentrated, then purified by flash chromatography using 20% DCM in MeOH. LCMS calculated for C17H22N7O3S (M+H)+m / z = 404.1; found 404.1. Step 2: l-( 1 -cyclohexylethyl) -4-( ( I -methyl-lH-pyrazol-4-yl)methyl)-N-( I - methylcyclopropyl) -5 -oxo-4, 5-dihydro-[ 1, 2, 4 ]triazolo[ 4, 3 -a quinazoline- 7- sulfonamide

[0655] To a mixture of 2-hydrazineyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-4-oxo-3,4-dihydroquinazoline-6-sulfonamide (10 mg, 0.02 mmol) in EtOH (0.5 mL) was added 2-cyclohexylpropanal (10 mg, 0.07 mmol) at rt. The resulting mixture was stirred at 50 °C for 2 h, then added FeCh (10 mg, 0.06 mmol). The resulting mixture was heated at 90 °C for 30 min before diluted with MeOH and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C26H34N7O3S (M+H)+m / z = 524.2; found 524.2.

[0656] Example 46. 9-Fluoro-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-5-oxo-4,5-dihydro-[l,2,4]triazolo[l,5-a]quinazoline-7- sulfonamide

[0657] Step 1: 5-(chlorosulfonyl)-2,3-difhiorobenzoic acid

[0658] To 100 mL of chlorosulfonic acid was added 2,3 -difluorobenzoic acid (25 g, 150 mmol) in portions at rt. The mixture was then heated to 140 °C for 3 h. The mixture was allowed to cool to rt, then added dropwise onto ice. The precipitated solid was collected via filtration then dried to afford the desired product as a beige solid. Step 2: 2,3-difluoro-5-(N-(l-methylcyclopropyl)sulfamoyl)benzoic acid

[0659] To a solution of 1-methylcyclopropanamine hydrochloride (8.6 g, 80 mmol) in dioxane / EEO (5: 1, 400 mL) was added DIPEA (38 mL, 218 mmol), followed by 5- (chlorosulfonyl)-2,3-difluorobenzoic acid (20 g, 80 mmol) in portions at rt. The reaction mixture was stirred for 2 h. The reaction was then concentrated and diluted with water and IN NaOH solution. The mixture was then extracted with Et2O (2x). The aqueous phase was acidified with 4N HC1 and extracted with EtOAc. The combined organic layers were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0660] Step 3: N-(5-bromo-lH-l,2,4-triazol-3-yl)-2,3-difluoro-5-(N-(l- methylcyclopropyl)sulfamoyl)benzamide

[0661] To a solution of 2,3-difluoro-5-(N-(l-methylcyclopropyl)sulfamoyl)benzoic acid (2.0 g, 6.87 mmol) and 5-bromo-lH-l,2,4-triazol-3-amine (1.23 g, 7.55 mmol) in THF was added HATU (8.74 g, 13.7 mmol) followed by DIPEA (2.34 mL, 13.7 mmol). The reaction mixture was stirred at 50 °C for 2h before quenching with sat. NaHCCE solution. The mixture was extracted with EtOAc (2x), the combined organic fractions were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was redissolved in EtOAc and added hexanes. The resulting suspension was stirred at rt overnight. The precipitate solid was collected as pure product and used in the next step without further purification. LCMS calculated for CBHBB^NSOSS (M+H)+m / z = 436.0; found 436.0. Step 4: 2-bromo-9-fluoro-N-( 1 -methylcyclopropyl)-5-oxo-4, 5-dihydro- [1,2,4 ]triazolo[ 1, 5 -a [quinazoline- 7 -sulfonamide

[0662] To a solution of N-(5-bromo-lH-l,2,4-triazol-3-yl)-2,3-difluoro-5-(N-(l- methylcyclopropyl)sulfamoyl)benzamide (2.0 g, 4.6 mmol) in NMP (25 mL) was added DIPEA (1.8 mL, 9.7 mmol) at rt. The mixture was then heated to 140 °C for 2h. The mixture was allowed to cool to rt and then added to a cold 0.5 N HC1 solution (300 mL). The solid precipitate was collected via filtration and dried to afford the desired product as a beige solid. LCMS calculated for CisHnBrFNsCLS (M+H)+m / z = 416.0; found 416.0.

[0663] Step 5: 2-bromo-9-jluoro-4-( 1 -methyl-lH-pyrazol-4-yl)methyl)-N-( 1 - methylcyclopropyl) -5 -oxo-4, 5-dihydro-[ 1, 2, 4 ]triazolo[ 1, 5-a]quinazoline- 7- sulfonamide

[0664] To a mixture of 2-bromo-9-fluoro-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydro-[l,2,4]triazolo[l,5-a]quinazoline-7-sulfonamide (1600 mg, 3.8 mmol) in DMF (20 mL) was added 4-(bromomethyl)-l-methyl-lH-pyrazole hydrobromide (1.47 g, 5.8 mmol), LiBr (668 mg, 7.7 mmol) and K2CO3 (5.0 g, 15.3 mmol). The resulting mixture was stirred at rt overnight. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic fractions were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified using flash column chromatography, eluting with 0-6% MeOH in DCM to afford the desired product as a light brown solid. LCMS calculated for CisHisBrFNvChS (M+H)+m / z = 510.0; found 510.0.

[0665] Step 6: 9-fluoro-4-( ( 1 -methyl-lH-pyrazol-4-yl)methyl)-N-( I -methylcyclopropyl)-5- oxo-4, 5-dihydro-[ 1,2,4 ]triazolo[ 1,5 -a quinazoline- 7 -sulfonamide

[0666] To a mixture of2-bromo-9-fluoro-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N- (l-methylcyclopropyl)-5-oxo-4,5-dihydro-[l,2,4]triazolo[l,5-a]quinazoline-7- sulfonamide (10 mg, 0.02 mmol) and Pd / C (10% 10 mg) in MeOH (0.5 mL) was purged with hydrogen. After stirring for 20 min, the reaction was diluted with MeOH and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C18H19FN7O3S (M+H)+ m / z = 432.1 ; found 432.1.

[0667] Example 47. 3-Methyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-l-(4-methylpiperazin-l-yl)-5-oxo-4,5-dihydro-3H- pyrazolo [3,4-c] isoquinoline-7-sulfonamide

[0668] Step 1: 5-(chlorosulfonyl)-2-iodobenzoic acid

[0669] A solution of 2-iodobenzoic acid (20.0 g, 76.3 mmol) was heated in chlorosulfonic acid (2.1 M) at 120 °C for 4 hours. Upon cooling to room temperature, the mixture was carefully poured into ice / water. The precipitated solids were collected via filtration and washed with water. The resulting solids were dried under vacuum to afford the desired product, which was used in the next step without further purification.

[0670] Step 2: 2-iodo-5-(N-(l-methylcyclopropyl)sulfamoyl)benzoic acid

[0671] To a solution of 1-methylcyclopropanamine hydrochloride (6.11 g, 56.8 mmol) in dioxane / TEO (5: 1) was added N, -diethylethanamine (21.5 mL, 155 mmol) followed by 5-(chlorosulfonyl)-2-iodobenzoic acid (17.9 g, 51.7 mmol) in portion at rt, then the reaction mixture was stirred at rt for 2 h. The reaction was then concentrated and diluted with water and IN NaOH solution which was then extracted with Et2O (2x). The aqueous phase was acidified with 4N HC1 and extracted with EtOAc. The combined organics were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS calculated for C11H13INO4S (M+H)+m / z =382.0; found 382.0.

[0672] Step 3: methyl 2-iodo-5-(N-(l-methylcyclopropyl)sulfamoyl)benzoate

[0673] To the solution of 2-iodo-5-[(l-methylcyclopropyl)sulfamoyl]benzoic acid (4.80 g, 12.6 mmol) in anhydrous DCM (0.5 M) was added oxalyl chloride (1.62 mL, 18.9 mmol) and 7V,7V-dimethylformamide (97.5 mL, 1.26 mmol) at rt. The resulting mixture was stirred at room temperature for 30 min. The reaction was quenched with methanol (0.51 mL, 12.6 mmol). The mixture was washed with water (50 mL) and brine, dried with sodium sulfate. The crude was purified with silica gel chromatography, eluting from 0-100% ethyl acetate / hexanes to give desired product. LCMS calculated for C12H15INO4S (M+H)+m / z =396.0; found 396.0. Step 4: methyl 2-iodo-5-(N-(l-methylcyclopropyl)-N-((2-

[0674] ( trimethylsilyl)ethoxy)methyl)suljamoyl) benzoate

[0675] To a solution of methyl 2-iodo-5-(N-(l- methylcyclopropyl)sulfamoyl)benzoate (3.73 g, 9.44 mmol) in anhydrous DMF (0.25 M) was added sodium hydride (0.45 g, 11.3 mmol) followed by 2- (chloromethoxy)ethyl-trimethyl-silane (2.01 mL, 11.3 mmol). The resulting brown suspension was stirred at rt for 1 hour. The reaction was quenched with water then extracted with ethyl acetate (100 mL x 2). The combined organic fractions were washed with water (x 3), followed by brine. The concentrated crude material was purified with silica gel, eluting from 0-100% ethyl acetate / hexanes to give light yellow oil. LCMS calculated for CistfelNOsSSi (M+H)+m / z = 526.1; found (M- HOCH2CH2TMS)+= 408.0.

[0676] Step 5: N-(3-bromo-l-methyl-lH-pyrazol-5-yl)-2-iodo-5-(N-( I -methylcyclopropyl)-N-

[0677] Under nitrogen, to a solution of 5-bromo-2-methyl-pyrazol-3-amine (0.74 g, 4.19 mmol) in anhydrous THF was added 1 M solution ofNaHMDS in THF (3.81 mL, 3.81 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 15 min. To the above solution was added a THF solution of methyl 2-iodo-5-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)benzoate (2.00 g, 3.81 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 15 min. LCMS analysis indicated that the reaction was complete. The reaction mixture was diluted with di chloromethane, washed with water and brine, dried with sodium sulfate. The crude was purified with silica gel, eluting from 0-100% ethyl acetate / hexanes to give desired product was light yellow solid. LCMS calculated for C2iH3iBrIN4O4SSi

[0678] (M+H) m / z = 669.0; found (M-HOCH2CH2TMS) = 550.9.

[0679] Step 6: N-(3-bromo-l-methyl-lH-pyrazol-5-yl)-2-iodo-N-((l-methyl-lH-pyrazol-4- yl)methyl)-5-(N-( I -methylcyclopropyl)-N-((2-

[0680] ( trimethylsilyl)ethoxy)methyl)sulfamoyl) benzamide

[0681] At 0 °C, to a solution of N-(3-bromo-l-methyl-lH-pyrazol-5-yl)-2-iodo-5-(N- (l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)benzamide (1.82 g, 2.72 mmol) and 4-(chloromethyl)-l-methyl-pyrazole (0.35 g, 2.72 mmol) in anhydrous DMF (0.5 M) was added potassium carbonate (0.75 g, 5.44 mmol) and lithium bromide (0.47 g, 5.44 mmol). The resulting mixture was heated at 45 °C for 2 hours. Upon completion of the reaction, the mixture was diluted with di chloromethane, washed with water 2 times followed by brine, dried with sodium sulfate. The crude was purified with silica gel chromatography, eluting with ethyl acetate / hexanes from 0-100% to give desired product as yellow solid. LCMS calculated for C26H37BrINeO4SSi (M+H)+m / z =763.1; found 763.1.

[0682] Step 7: l-bromo-3-methyl-4-( 1 -methyl-lH-pyrazol-4-yl)methyl)-N-( 1 - methylcyclopropyl)-5-oxo-N-( (2-( trimethylsilyl)ethoxy)methyl)-4, 5-dihydro-3H- pyrazolo[ 3, 4-c ]isoquinoline-7-sulfonamide

[0683] To a vial was added A-(3-bromo-l-methyl-U / -pyrazol-5-yl)-2-iodo-7V-((l- methyl-U / -pyrazol-4-yl)methyl)-5-(A-(l-methylcyclopropyl)-A-((2- (trimethylsilyl)ethoxy)methyl)sulfamoyl)benzamide (1.67 g, 1.60 mmol), potassium acetate (0.47 g, 4.79 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.37 g, 0.32 mmol). The vial was then sealed then evacuated and backfilled with N2 three times. To the enclosed system was added DMAc (0.1 M) at rt. The resulting suspension was heated at 105 °C for 3 hours. The mixture was cooled to rt, diluted with EtOAc, and washed with water 4 times. The organic layer was dried with sodium sulfate, concentrated under reduced pressure. The crude material was purified with silica gel, eluting with 0-100% EA / Hexanes to give desired product as a light yellow solid. LCMS calculated for C26H36BrNeO4SSi (M+H)+m / z = 635.1; found (M- HOCH2CH2TMS)+= 517.0.

[0684] Step 8: 3-methyl-4-( ( 1 -methyl- lH-pyrazol-4-yl)methyl)-N-( I -methylcyclopropyl)-! -(4- methylpiperazin-l-yl)-5-oxo-4, 5-dihydro-3H-pyrazolo[ 3, 4-c ] isoquinoline- 7- sulfonamide

[0685] To the solution of l-bromo-3-methyl-4-((l -methyl- l / / -pyrazol-4-yl)methyl)- A-(l-methylcyclopropyl)-5-oxo-A-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro- 3 / / -pyrazolo[3,4-c]isoquinoline-7-sulfonamide (20.6 mg, 32.4 mmol) in anhydrous THF (0.4 M) was added GPhos Pd G6 (3.06 mg, 32.4 pmol), 1 -methylpiperazine (4.32 pL, 0.04 mmol) and sodium trimethyl silanolate (4.00 mg, 0.04 mmol) at room temperature. The resulting mixture was heated at 55 °C overnight. The mixture was cooled to room temperature and the crude reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure to give a brown oil, which was applied to a 1 to 1 mixture of trifluoroacetic acid and dichloromethane at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. Upon completion of the reaction, the crude was purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C25H33N8O3S (M+H)+m / z = 525.2; found 525.2. Example 48. 9-Chloro-3-methyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinoline-7- sulfonamide

[0686] Step 1: 5-bromo-2-iodo-N-(l-methyl-lH-pyrazol-5-yl)benzamide

[0687] At 0 °C, to a solution of 5-bromo-2-iodo-benzoic acid (30.00 g, 91.77 mmol) in DMF (0.67 M) was added 2-methylpyrazol-3 -amine (9.80 g, 100.9 mmol) , HATU (41.9 g, 110.1 mmol) and DIPEA (32.05 mL, 183.5 mmol). The resulting solution was stirred at room temperature for 3 hours. Water (lOx volume of DMF) was added into the reaction at room temperature to give white color precipitate. The solids were collected via filtration. The resulting solid was suspended in water and heated at 50 C for 1 hour. The solids were collected via filtration, then washed with heptane 5 times to give desired product (33.50 g, 89.9%) as white solid. LCMS calculated for CnHioBrlNsO (M+H)+m / z = 405.9; found 405.8.

[0688] Step 2: 5-bromo-2-iodo-N-(l-methyl-lH-pyrazol-5-yl)-N-((2- ( trimethylsilyl)ethoxy)methyl) benzamide

[0689] At -10 °C, to a solution of 5-bromo-2-iodo-N-(l-methyl-lH-pyrazol-5- yl)benzamide (5.25 g, 12.93 mmol) in anhydrous DMF (0.5 M) was added sodium hydride (0.62 g, 15.52 mmol) slowly. The resulting mixture was stirred at 0 °C for 15 min, followed by the addition of 2-(chloromethoxy)ethyl-trimethyl-silane (2.75 mL, 15.52 mmol). The mixture was stirred at room temperature overnight. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate (200 mL), washed with water (50 mL x 4). The organic layer was dried with sodium sulfate. The crude was purified with silica gel chromatography, eluting with ethyl acetate / hexanes from 0-50% to give desired product (5.27 g, 76.0%) as a colorless oil. LCMS calculated for CnfMrINsChSi (M+H)+m / z = 536.0; found 535.9.

[0690] Step 3: 7-bromo-3-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-3, 4-dihydro-5H- pyrazolo[ 3, 4-c ] isoquinol in-5 -one

[0691] To a vial was added 5-bromo-2-iodo-N-(l -methyl- lH-pyrazol-5-yl)-N-((2- (trimethylsilyl)ethoxy)methyl)benzamide (5.27 g, 7.17 mmol), potassium acetate (2.11 g, 21.52 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.66 g, 1.43 mmol). The vial was sealed then evacuated and backfilled with N23 times. To the closed system was added DMAc (20.0 mL * 10, 0.1 M) at room temperature. The resulting suspension was heated at 100 °C for 2 hours. LCMS analysis indicated that the reaction was complete. The reaction mixture was cooled to room temperature, then filtered through Celite. The filtrate was diluted with ethyl acetate (100 mL), washed with water (50 mL x 4), dried with sodium sulfate. The crude residue was purified with silica gel chromatography, eluting from 0-100% ethyl acetate / DCM to give yellow solid as desired product. LCMS calculated for CnH^BrNsCLSi (M+H)+m / z = 408.1; found 408.1.

[0692] Step 4: 7-(benzylthio)-3-methyl-4-( (2-(trimethylsilyl)ethoxy)methyl)-3, 4-dihydro-5H- pyrazolo[ 3, 4-c ] isoquinol in-5 -one

[0693] To a mixture of 7-bromo-3-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-3,4- dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one (2.93 g, 7.17 mmol) and phenyl methanethiol (1.68 mL, 14.4 mmol) in anhydrous dioxane (0.25 M) was added tris(dibenzylideneacetone)dipalladium(0) ( 0.33 g, 0.36 mmol) and XantPhos (0.42 g, 0.72 mmol) under N2, followed by DIPEA (3.76 mL, 21.52 mmol). The mixture solution was evacuated and backfilled with N2 three minutes, then sealed and heated at 90 °C for 5 hours. Upon completion of reaction, the mixture was cooled to rt. The precipitate was filtered over celite, then the filtrate was concentrated onto silica gel (20 g), purified with silica gel chromatography, eluting with 20% ethyl acetate / hexanes to give desired product as orange solid. LCMS calculated for C24H3oN302SSi (M+H)+m / z = 452.2; found 452.2.

[0694] Step 5: 3-methyl-N-(l-methylcyclopropyl)-5-oxo-4-((2-(trimethylsilyl)ethoxy)methyl)- 4, 5-dihydro-3H-pyrazolo[ 3, 4-c ] isoquinoline- 7 -sulfonamide

[0695] To the solution of 7-(benzylthio)-3-methyl-4-((2- (trimethylsilyl)ethoxy)methyl)-3,4-dihydro-5H-pyrazolo[3,4-c]isoquinolin-5-one (3.87 g, 8.57 mmol) in a 20 / 2 / 1 mixture of AcN / AcOH / water at 0 °C was added 1,3- dichloro-5,5-dimethyl-imidazolidine-2, 4-dione (2.19 g, 11.1 mmol). The resulting mixture was stirred at 0 °C for 1 hour. The solvent was removed under reduced pressure, and the residue was put under vacuum for another 30 min. To a suspension of 1-methylcyclopropanamine hydrochloride (1.20 g, 11.1 mmol) in AcN was added potassium carbonate (7.11 g, 51.4 mmol) at 0 °C. To the resulting clear solution was added the suspension of intermediate in AcN at 0 C. The resulting solution was stirred at rt for 1 hour. The reaction was diluted with DCM (200 mL), washed with water (50 mL x 3). The organic layer was combined and dried with sodium sulfate. The crude was purified with silica gel, eluting from 0-100% ethyl acetate / DCM to give desired product (2.58 g, 65.1%) as white solid. LCMS calculated for C2iH3iN4O4SSi (M+H)+m / z =463.2; found 463.1.

[0696] Step 6: tert-butyl ((3-methyl-5-oxo-4-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-

[0697] At -10 °C, to a solution of 3-methyl-N-(l-methylcyclopropyl)-5-oxo-4-((2- (trimethylsilyl)ethoxy)methyl)-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinoline-7- sulfonamide (2.58 g, 5.58 mmol) in anhydrous DMF (0.5 M) was added sodium hydride (0.45 g, 11.2 mmol) slowly. The resulting mixture was stirred at 0 °C for 15 min, followed by addition of BOC2O (3.04 g, 13.94 mmol). The mixture was stirred at rt for 2 hours. The reaction was then quenched with water, extracted with DCM (100 mL x 3), the combined organic layer was dried with sodium sulfate. The crude was purified with silica gel column, 120 g, eluting with EA / Hexanes to give desired product (3.00 g, 95.6 %) as white solid. LCMS calculated for C26H39N40eSSi (M+H)+m / z =563.2; found 563.2.

[0698] Step 7: tert-butyl ((9-chloro-3-methyl-5-oxo-4-((2-(trimethylsilyl)ethoxy)methyl)-4,5- dihydro-3H-pyrazolo[ 3, 4-c ] isoquinolin- 7 -y I) sulfonyl) (1- methylcyclopropyl)carbamate

[0699] To a solution of tert-butyl ((3-methyl-5-oxo-4-((2- (trimethylsilyl)ethoxy)methyl)-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-7- yl)sulfonyl)(l-methylcyclopropyl)carbamate (1.00 g, 1.78 mmol) in ACN (0.01 M) was added 1 -chloropyrrolidine-2, 5-dione (0.71 g, 5.33 mmol, 3.0 eq) and acetic acid (304.9 pL, 5.33 mmol, 3.0 eq) at rt. The resulting clear solution was vigorously stirred at 60 °C overnight. Upon completion of reaction, the solvent was removed under reduced pressure. The residue was purified with silica gel chromatography, eluting with EA / Hexanes from 0-100%, give desired product (0.39 g, 36.4 %) as a light yellow solid. LCMS calculated for C26H38ClN40eSSi (M+H)+m / z = 597.2; found 597.2. Step 8: tert-butyl ((9-chloro-3-methyl-5-oxo-4,5-dihydro-3H-pyrazolo[3,4- c ] isoquinolin- 7 -y I) sulfonyl) ( I -methylcyclopropyl) carbamate

[0700] To a solution of tert-butyl ((9-chloro-3-methyl-5-oxo-4-((2- (trimethylsilyl)ethoxy)methyl)-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinolin-7- yl)sulfonyl)(l-methylcyclopropyl)carbamate (257.60 mg, 0.43 mmol) in anhydrous THF (0.8 M) was added tetrabutylammonium fluoride (2.59 mL, 2.59 mmol) at room temperature. The mixture was heated at 70 °C for 2 hours. The mixture was diluted with EA, washed with water, sat. NaHCCh and brine, dried with sodium sulfate. The crude material was purified with silica gel chromatography, eluting with ethyl acetate / DCM to give desired product as yellow solid (84.9 mg, 42.2 %). LCMS calculated for C2oH24ClN405SNa (M+H)+m / z = 467.1; found (M+Na) = 489.0.

[0701] Step 9: tert-butyl ((9-chloro-3-methyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-5-oxo- 4, 5-dihydro-3H-pyrazolo[ 3, 4-c ] isoquinolin- 7 -y I) sulfonyl) (1- methylcyclopropyl)carbamate

[0702] To a suspension of tert-butyl ((9-chloro-3-methyl-5-oxo-4,5-dihydro-3H- pyrazolo[3,4-c]isoquinolin-7-yl)sulfonyl)(l-methylcyclopropyl)carbamate (84.90 mg, 0.18 mmol) in DMF was added potassium carbonate (75.4 mg, 0.55 mmol), 4- (chloromethyl)-l-methyl-pyrazole (23.7 mg, 0.18 mmol) and lithium bromide (31.6 mg, 0.36 mmol) at rt for 2 hours. The reaction mixture was diluted with EA, washed with water, sat. NaHCCh and brine, dried with sodium sulfate. The crude mixture was purified with silica gel chromatography, eluting with ethyl acetate / DCM to give desired product as yellow solid (59.6 mg, 39.6%) . LCMS calculated for C25H30CIN6O5S (M+H)+m / z = 561.2; found 561.1.

[0703] Step 10: 9-chloro-3-methyl-4-( 1 -methyl-lH-pyrazol-4-yl)methyl)-N-( I - methylcyclopropyl) -5-oxo-4, 5-dihydro-3H-pyrazolo[ 3, 4-c ] isoquinoline- 7 -sulfonamide tert-Butyl ((9-chloro-3-methyl-4-((l -methyl- lH-pyrazol-4-yl)methyl)-5-oxo- 4, 5 -dihy dro-3H-pyrazolo [3 , 4 - c] i soquinolin-7 -yl)sulfonyl)( 1 - methylcyclopropyl)carbamate (10.0 mg, 0.02 mmol) was treated with a 1 to 1 mixture of TFA and DCM at rt. The mixture was heated at 40 °C for 30 min. The crude mixture was purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C20H22CIN6O3S (M+H)+m / z = 461.1; found 461.1.

[0704] Example 49. (R)-4-(3-Ethyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)-

[0705] N,N,2-trimethylpiperazine-l-carboxamide

[0706] Step 1: Tert-butyl 3-(2,3-dijluoro-5-(N-(l-methylcyclopropyl)sulfamoyl)benzamido)- IH-pyrazole-l -carboxylate To a mixture of 2,3-difluoro-5-(7V-(l-methylcyclopropyl)sulfamoyl)benzoic acid (as prepared in Example 46, Step 2, 3.3 g, 11 mmol) and tert-butyl 3- aminopyrazole-1 -carboxylate (2.7 g, 14.7 mmol) in tetrahydrofuran (40 mL) were added propanephosphonic acid cyclic anhydride (50% in ethyl acetate) (7.21 g, 22.7 mmol) and 7V,7V-diisopropylethylamine (14.64 g, 113.3 mmol) at room temperature. The resulting mixture was stirred at 50 °C for 2 h. Upon cooling to room temperature, the resulting mixture was quenched with water (150 mL). The resulting mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (300 mL), water (300 mL), brine (300 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 50% ethyl acetate in petroleum ether to afford the desired product as a light yellow solid (3.2 g, 62%). LCMS calculated for C19H21F2N4O5S (M-H)- m / z = 455.1; found 455.1.

[0707] Step 2: 2, 3-Difluoro-5-(N-( 1 -methylcyclopropyl) sulfamoyl) -N-( lH-pyrazol-3- y I) benzamide

[0708] To a mixture of tert-butyl 3-(2,3-difluoro-5-(7V-(l- methylcyclopropyl)sulfamoyl)benzamido)- IT / -pyrazole- l -carboxylate (3 g, 6.6 mmol) in dichloromethane (30 mL) was added hydrochloric acid (4.0 M in 1,4-dioxane, 10 mL). The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 10% methanol in di chloromethane to afford the desired product as a white solid (2 g, 86%). LCMS calculated for C14H15F2N4O3S (M+H)+m / z = 357.1; found 357.0.

[0709] Step 3: 9-Fluoro-N-( I -methylcyclopropyl)-5-oxo-4, 5-dihydropyrazolo[ 1, 5- a quinazoline- 7 -sulfonamide

[0710] A mixture of 2,3-difluoro-5-(A-(l-methylcyclopropyl)sulfamoyl)-7V-(lJ7- pyrazol-3-yl)benzamide (3.5 g, 9.8 mmol) and potassium carbonate (9.6 g, 29.5 mmol) in V,V-dimethylformamide (500 mL) was stirred at 110 °C for 1 h. Upon cooling to room temperature, the resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in acetonitrile in water (0.1% trifluoroacetic acid), 10% to 50% gradient in 20 min; detector, UV 254 nm. Fractions were collected and concentrated to provide the desired product as a white solid (2 g, 60%). LCMS calculated for C14H12FN4O3S (M-H)' m / z = 335.1; found 334.9.

[0711] Step 4: 9-Fluoro-4-( 1 -methyl-lH-pyrazol-4-yl)methyl)-N-( I -methylcyclopropyl)-5- oxo-4, 5-dihydropyrazolo[ 1, 5 -a quinazoline- 7 -sulfonamide

[0712] To a mixture of 9-fluoro-7V-(l-methylcyclopropyl)-5-oxo-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide (500 mg, 1.49 mmol), lithium bromide (258 mg, 3.0 mmol) and potassium carbonate (822 mg, 5.95 mmol) in N,N- dimethylformamide (5 mL) was added 4-(brom om ethyl)- 1 -methyl- UT-pyrazole hydrobromide (460 mg, 1.78 mmol). The reaction mixture was stirred at room temperature for 3 h. The resulting mixture was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, acetonitrile in water (0.1% formic acid), 40% to 70% gradient over 20 min; detector, UV 254 nm. Fractions were collected and concentrated to provide the desired product as a white solid (300 mg, 47%). LCMS calculated for C19H20FN6O3S (M+H)+m / z = 431.1; found 431.2.

[0713] Step 5: (R)-N,N, 2-trimethyl-4-( 4-( 1 -methyl-lH-pyrazol-4-yl)methyl)~ 7-(N-( 1 - methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9- yl)piperazine-l -carboxamide

[0714] To a stirred mixture of 9-fluoro-4-((l -methyl- lJ / -pyrazol-4-yl)methyl)-7V-(l- methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide (300 mg, 0.7 mmol) and (27?)-7V,7V,2-trimethylpiperazine-l -carboxamide (239 mg, 1.4 mmol) in dimethyl sulfoxide (3 mL) was added N, / f-diisopropylethylamine (180 mg, 1.4 mmol). The resulting mixture was stirred at 90 °C for 16 h. Upon cooling to room temperature, the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (10 mmol / L ammonium bicarbonate), 15% to 50% gradient over 25 min; detector, UV 254 nm. Fractions were collected and concentrated to provide the desired product as an off-white solid (120 mg, 30%). LCMS calculated for C27H36N9O4S (M+H)+m / z = 582.3; found 582.2.

[0715] Step 6: (R)-4-(3-bromo-4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)-

[0716] N,N,2-trimethylpiperazine-l-carboxamide

[0717] To a mixture of (7?)-7V,7V,2-trimethyl-4-(4-((l-methyl-17 / -pyrazol-4- yl)methyl)-7-(7V-(l-methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5- a]quinazolin-9-yl)piperazine-l -carboxamide (120 mg, 0.21 mmol) and acetic acid (25 mg, 0.4 mmol) in acetonitrile (2 mL) was added 7V-bromosuccinimide (55 mg, 0.31 mmol). The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 10% methanol in di chloromethane to afford the desired product a yellow solid (100 mg, 74%). LCMS calculated for C27H35BrN9O4S (M+H)+m / z = 660.2; found 660.1.

[0718] Step 7: (R)-N,N, 2-trimethyl-4-( 4-( 1 -methyl-lH-pyrazol-4-yl)methyl)~ 7-(N-( 1 - methylcyclopropyl)sulfamoyl)-5-oxo-3-vinyl-4, 5-dihydropyrazolo[ 1, 5-a]quinazolin-9- yl)piperazine-l -carboxamide

[0719] To an 8 mL vial were placed (7?)-4-(3-bromo-4-((l-methyl-17 / -pyrazol-4- yl)methyl)-7-(7V-(l-methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5- a]quinazolin-9-yl)-7V,7V,2-trimethylpiperazine-l -carboxamide (100 mg, 0.15 mmol), 2- ethenyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (35 mg, 0.23 mmol), Pd(dppf)C12CH2C12 (12 mg, 0.01 mmol) and potassium carbonate (63 mg, 0.45 mmol). The vial was sealed with a Teflon-lined septum, evacuated and backfilled with nitrogen (this process was repeated a total of three times). 1,4-Dioxane (2.5 mL) and water (0.5 mL) were added. The resulting mixture was stirred at 80 °C for 2 h. Upon cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 10% methanol in di chloromethane to afford the desired product as a yellow solid (60 mg, 65%). LCMS calculated for C29H38N9O4S (M+H)+m / z = 608.3; found 608.4.

[0720] Step 8: (R)-4-(3-ethyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)- N,N,2-trimethylpiperazine-l-carboxamide

[0721] To an 8 mL vial were placed (7?)-7V,7V,2-trimethyl-4-(4-((l-methyl-U / -pyrazol- 4-yl)methyl)-7-(7V-(l-methylcyclopropyl)sulfamoyl)-5-oxo-3-vinyl-4,5- dihydropyrazolo[l,5-a]quinazolin-9-yl)piperazine-l-carboxamide (40 mg, 0.07 mmol), methanol (2 mL) and Pd / C (14 mg, 0.013 mmol, 10%). The vial was sealed with a Teflon-lined septum, evacuated and backfilled with hydrogen (this process was repeated a total of three times). The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (10% methanol in di chloromethane) and then purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, acetonitrile in water (0.1% formic acid), 5% to 95% gradient in 20 min; detector, UV 254 nm. Fractions were collected and lyophilized to provide the desired product as a white solid (7.4 mg, 17%). LCMS calculated for C29H40N9O4S (M+H)+m / z = 610.3; found 610.4. 'H NMR (400 MHz, DMSO-t / 6) 8 8.30 (d, J= 2.0 Hz, 1H), 8.22 (s, 1H), 7.91 (s, 1H),

[0722] 7.77 (d, J= 2.0 Hz, 1H), 7.64 (s, 1H), 7.40 (s, 1H), 5.30 - 5.16 (m, 2H), 4.08 - 3.95 (m, 1H), 3.75 (s, 3H), 3.71 - 3.61 (m, 1H), 3.29 - 3.18 (m, 3H), 3.09 - 2.97 (m, 1 H),

[0723] 2.78 (s, 6H), 2.67 (q, J= 7.6 Hz, 2H), 2.55 - 2.53 (m, 1 H), 1.43 - 1.31 (m, 3H), 1.18 (t, J= 7.6 Hz, 3H), 1.07 (s, 3H), 0.67 - 0.60 (m, 2H), 0.45 - 0.38 (m, 2H). Example 50. (R)-N,N,2-Trimethyl-4-(3-(l-methyl-lH-pyrazol-4-yl)-4-((l-methyl- lH-pyrazol-4-yl)methyl)-7-(N-(l-methylcyclopropyl)sulfamoyl)-5-oxo-4,5- dihydropyrazolo[l,5-a]quinazolin-9-yl)piperazine-l-carboxamide

[0724] To an 8 mL vial were placed (A)-4-(3-bromo-4-((l-methyl-l / / -pyrazol-4- yl)methyl)-7-(7V-(l-methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5- a]quinazolin-9-yl)-7V,A,2-trimethylpiperazine-l -carboxamide (100 mg, 0.15 mmol), 1- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (63 mg, 0.3 mmol), Pd(dppf)C12CH2C12 (12 mg, 0.01 mmol) and potassium carbonate (63 mg, 0.45 mmol). The vial was sealed with a Teflon-lined septum, evacuated and backfilled with nitrogen (this process was repeated a total of three times). 1,4-Dioxane (2.5 mL) and water (0.5 mL) were added. The resulting mixture was stirred at 60 °C for 2 h. Upon cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 10% methanol in di chloromethane and then purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: acetonitrile in water (10 mmol / L ammonium bicarbonate); Flow rate: 60 mL / min; Gradient: 22% B to 52% B in 10 min; Wave Length: 254nm / 220nm nm). Fractions were collected and lyophilized to provide the desired product as a white solid. (14.6 mg, 14%) as a white solid. LCMS calculated for C31H40N11O4S (M+H)+m / z = 662.3; found 662.4.1H NMR (400 MHz, DMSO-t / 6) 8 8.31 (d, J= 2.0 Hz, 1H), 8.24 (s, 1H), 7.87 (s, 1H), 7.80 (d, J= 2.0 Hz, 1H), 7.73 (s, 1H), 7.49 (s, 1H), 7.28 (s, 1H), 6.92 (s, 1H), 5.18 - 5.02 (m, 2H), 4.08 - 3.96 (m, 1H), 3.89 (s, 3H), 3.76-3.60 (m, 4H), 3.29 - 3.20 (m, 3H), 3.08 - 3.00 (m, 1H), 2.89 - 2.71 (s, 7H), 1.44 - 1.32 (m, 3H), 1.07 (s, 3H), 0.67 - 0.60 (m, 2H), 0.45 - 0.39 (m, 2H). Example A. Cellular PARG Inhibition Assay

[0725] The purpose of this assay was to determine the potency of the PARG inhibitors described in the Examples. HeLa cells (ATCC, CCL-2) were seeded into 96 well plate at 25000 cells / well and incubated for 24 h. Cells were pre-incubated with test compound for 1 h, stimulated with 50 pg / mL methyl methanesulfonate (MMS) for an additional 1 h, then the cells were fixed in 100% ice-cold methanol for 20 min. After fixation, cells were washed in lx PBST 3 times, (5 min each), then cells were blocked in blocking buffer (10% goat serum, 1% BSA, 0.1% Triton X-100, in PBST) for 1 h at room temperature, and then incubated with mouse anti-PAR primary antibody (Adipogen, AG-20T-0001-M001, 1 :300 in blocking buffer) for 18 h at 4 °C. Plates were then washed in lx PBST 3 times (5 min each), incubated with IRDye 800CW conjugated goat anti -mouse IgG secondary antibody (LI-COR, 926-32210, 1 : 1000 in blocking buffer) for 1 h at room temperature, and then the plates were washed 3 times in lx PBST (5 min each). Infrared signal was measured using the LI- COR Odyssey DLx Imaging system. Data was analyzed using GraphPad Prism.

[0726] Results of the PARG inhibition assay are presented in Table A. “++++” indicates an IC50 less than 1000 nM; “+++” indicates an IC50 greater than or equal to 1000 nM but less than 5000 nM; “++” indicates an IC50 greater than or equal to 5000 nM but less than 10000 nM; and “+” indicates an IC50 greater than or equal to 10000 nM.

[0727] Table A.

[0728] Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:= is a single or double bond; n is 0, 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6;X is C or N;Y is C or N;Z is O or NR4;Ring A is phenyl, or 5-6 membered heteroaryl;X1is N or CR5;X2is N or CR6;X3is N or CR7;R1is selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-54057 -0016W01 / SNV-0013W01 PATENT4 alkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;R2is selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)- C1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each R2Ais independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, - ORa2A, -SRa2A, -NRc2ARd2A, -NO2, -C(O)Ra2A, -C(O)ORa2A, -C(O)NRc2ARd2A, - C(O)NRc2A(ORa2A), -OC(O)Ra2A, -OC(O)NRc2ARd2A, -OC(O)ORa2A, -OS(O)2Rb2A, - OS(O)2NRc2ARd2A, -NRc2AC(O)Ra2A, -NRc2AC(O)ORa2A, -NRc2AC(O)NRc2ARd2A, - NRc2AS(O)2Rb2A, -NRc2AS(O)2NRc2ARd2A, -NRc2AORa2A, -NRc2AS(O)Rb2A, - NRc2AS(O)NRc2ARd2A, -S(O)Rb2A, -S(O)2Rb2A, -S(O)NRc2ARd2A, -S(O)2NRc2ARd2A, - C(=NRe2A)Ra2A, -C(=NRe2A)NRc2ARd2A, -NRc2AC(=NRe2A)Ra2A, - NRc2AC(=NRe2A)NRc2ARd2A, -NRc2AS(O)(=NRe2A)Rb2A, - NRc2AS(O)(=NRe2A)NRc2ARd2A, -OS(O)(=NRe2A)Rb2A, -S(O)(=NRe2A)Rb2A, - S(O)(=NRe2A)NRc2ARd2A, -C(O)NRc2AS(O)2Rb2A, -C(O)NRc2AS(O)2NRc2ARd2A, - S(O)2NRc2AC(O)Rb2A, -NRc2AS(O)NRc2AC(O)Rb2A, and -P(O)Rf2ARg2A, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra2A, Rc2A, and Rd2Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered54057 -0016W01 / SNV-0013W01 PATENT heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra2A, Rc2A, and Rd2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc2Aand Rd2Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb2Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re2Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each RI2and Rg2Aare independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;54057 -0016W01 / SNV-0013W01 PATENT each R3is independently selected from H, oxo, halo, Ci-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, -CN, -ORa3, -SRa3, -NRc3Rd3, -NO2, -C(O)Ra3, -C(O)ORa3, -C(O)NRc3Rd3, -S(O)2NRc3C(O)Rb3, -NRc3S(O)NRc3C(O)Rb3, and -P(O)RfiRg3, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Ra3, Rc3, and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra3, Rc3, and Rd3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; or, any Rc3and Rd3attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents;54057 -0016W01 / SNV-0013W01 PATENT each Rb3is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Re3is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl,4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Rfiand Rg3are independently selected from H, C1-6 alkyl, C1-6 alkoxy, Ci- 6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R3Ais independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, - ORa3A, -SRa3A, -NRc3ARd3A, -NO2, -C(O)Ra3A, -C(O)ORa3A, -C(O)NRc3ARd3A, - C(O)NRc3A(ORa3A), -OC(O)Ra3A, -OC(O)NRc3ARd3A, -OC(O)ORa3A, -OS(O)2Rb3A, - OS(O)2NRc3ARd3A, -NRc3AC(O)Ra3A, -NRc3AC(O)ORa3A, -NRc3AC(O)NRc3ARd3A, - NRc3AS(O)2Rb3A, -NRc3AS(O)2NRc3ARd3A, -NRc3AORa3A, -NRc3AS(O)Rb3A, - NRc3AS(O)NRc3ARd3A, -S(O)Rb3A, -S(O)2Rb3A, -S(O)NRc3ARd3A, -S(O)2NRc3ARd3A, - C(=NRe3A)Ra3A, -C(=NRe3A)NRc3ARd3A, -NRc3AC(=NRe3A)Ra3A, - NRc3AC(=NRe3A)NRc3ARd3A, -NRc3AS(O)(=NRe3A)Rb3A, - NRc3AS(O)(=NRe3A)NRc3ARd3A, -OS(O)(=NRe3A)Rb3A, -S(O)(=NRe3A)Rb3A, - S(O)(=NRe3A)NRc3ARd3A, -C(O)NRc3AS(O)2Rb3A, -C(O)NRc3AS(O)2NRc3ARd3A, -54057 -0016W01 / SNV-0013W01 PATENTS(O)2NRc3AC(O)Rb3A, -NRc3AS(O)NRc3AC(O)Rb3A, and -P(O)RfiARg3A, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra3A, Rc3A, and Rd3Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra3A, Rc3A, and Rd3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc3Aand Rd3Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb3Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re3Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-454057 -0016W01 / SNV-0013W01 PATENT alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each RfiAand Rg3Aare independently selected from H, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;R4is selected from H, CN, ORa4, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of R4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, R4and R1, together with the atoms to which they are attached, form a 5-10 membered heterocycloalkyl group, wherein the 5-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;Ra4is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3- 10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)- C1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra4is each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;R5is selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and -CN;54057 -0016W01 / SNV-0013W01 PATENTR6is selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and -CN;R7is selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, -S(O)2NRc7C(O)Rb7, -NRc7S(O)NRc7C(O)Rb7, and -P(O)RnRg7, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R7are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R7Asubstituents; each Ra7, Rc7, and Rd7is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra7, Rc7, and Rd7are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R7Asubstituents; or, any Rc7and Rd7attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the54057 -0016W01 / SNV-0013W01 PATENT4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R7Asubstituents; each Rb7is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb7are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R7Asubstituents; each Re7is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl,4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R17and Rg7are independently selected from H, C1-6 alkyl, C1-6 alkoxy, Ci- 6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R7Ais independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, - ORa7A, -SRa7A, -NRc7ARd7A, -NO2, -C(O)Ra7A, -C(O)ORa7A, -C(O)NRc7ARd7A, - C(O)NRc7A(ORa7A), -OC(O)Ra7A, -OC(O)NRc7ARd7A, -OC(O)ORa7A, -OS(O)2Rb7A, - OS(O)2NRc7ARd7A, -NRc7AC(O)Ra7A, -NRc7AC(O)ORa7A, -NRc7AC(O)NRc7ARd7A, - NRc7AS(O)2Rb7A, -NRc7AS(O)2NRc7ARd7A, -NRc7AORa7A, -NRc7AS(O)Rb7A, - NRc7AS(O)NRc7ARd7A, -S(O)Rb7A, -S(O)2Rb7A, -S(O)NRc7ARd7A, -S(O)2NRc7ARd7A, - C(=NRe7A)Ra7A, -C(=NRe7A)NRc7ARd7A, -NRc7AC(=NRe7A)Ra7A, - NRc7AC(=NRe7A)NRc7ARd7A, -NRc7AS(O)(=NRe7A)Rb7A, -54057 -0016W01 / SNV-0013W01 PATENTNRc7AS(O)(=NRe7A)NRc7ARd7A, -OS(O)(=NRe7A)Rb7A, -S(O)(=NRe7A)Rb7A, - S(O)(=NRe7A)NRc7ARd7A, -C(O)NRc7AS(O)2Rb7A, -C(O)NRc7AS(O)2NRc7ARd7A, - S(O)2NRc7AC(O)Rb7A, -NRc7AS(O)NRc7AC(O)Rb7A, and -P(O)RnARg7A, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R7Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra7A, Rc7A, and Rd7Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra7A, Rc7A, and Rd7Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc7Aand Rd7Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb7Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb7Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;54057 -0016W01 / SNV-0013W01 PATENT each Re7Ais independently selected from H, OH, CN, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each RnAand Rg7Aare independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;R8is selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and -CN;R9is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, - ORa9, -SRa9, -NRc9Rd9, -NO2, -C(O)Ra9, -C(O)ORa9, -C(O)NRc9Rd9, - C(O)NRc9(ORa9), -OC(O)Ra9, -OC(O)NRc9Rd9, -OC(O)ORa9, -OS(O)2Rb9, - OS(O)2NRc9Rd9, -NRc9C(O)Ra9, -NRc9C(O)ORa9, -NRc9C(O)NRc9Rd9, -NRc9S(O)2Rb9, -NRc9S(O)2NRc9Rd9, -NRc9ORa9, -NRc9S(O)Rb9, -NRc9S(O)NRc9Rd9, -S(O)Rb9, - S(O)2Rb9, -S(O)NRc9Rd9, -S(O)2NRc9Rd9, -C(=NRe9)Ra9, -C(=NRe9)NRc9Rd9, - NRc9C(=NRe9)Ra9, -NRc9C(=NRe9)NRc9Rd9, -NRc9S(O)(=NRe9)Rb9, - NRc9S(O)(=NRe9)NRc9Rd9, -OS(O)(=NRe9)Rb9, -S(O)(=NRe9)Rb9, - S(O)(=NRe9)NRc9Rd9, -C(O)NRc9S(O)2Rb9, -C(O)NRc9S(O)2NRc9Rd9, - S(O)2NRc9C(O)Rb9, -NRc9S(O)NRc9C(O)Rb9, and -P(O)R®Rg9, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R9are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R9Asubstituents; each Ra9, Rc9, and Rd9is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered54057 -0016W01 / SNV-0013W01 PATENT heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra9, Rc9, and Rd9are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R9Asubstituents; or, any Rc9and Rd9attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R9Asubstituents; each Rb9is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb9are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R9Asubstituents; each Re9is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R® and Rg9are independently selected from H, C1-6 alkyl, C1-6 alkoxy, Ci- 6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;54057 -0016W01 / SNV-0013W01 PATENT each R9Ais independently selected from oxo, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, - ORa9A, -SRa9A, -NRc9ARd9A, -NO2, -C(O)Ra9A, -C(O)ORa9A, -C(O)NRc9ARd9A, - C(O)NRc9A(ORa9A), -OC(O)Ra9A, -OC(O)NRc9ARd9A, -OC(O)ORa9A, -OS(O)2Rb9A, - OS(O)2NRc9ARd9A, -NRc9AC(O)Ra9A, -NRc9AC(O)ORa9A, -NRc9AC(O)NRc9ARd9A, - NRc9AS(O)2Rb9A, -NRc9AS(O)2NRc9ARd9A, -NRc9AORa9A, -NRc9AS(O)Rb9A, - NRc9AS(O)NRc9ARd9A, -S(O)Rb9A, -S(O)2Rb9A, -S(O)NRc9ARd9A, -S(O)2NRc9ARd9A, - C(=NRe9A)Ra9A, -C(=NRe9A)NRc9ARd9A, -NRc9AC(=NRe9A)Ra9A, - NRc9AC(=NRe9A)NRc9ARd9A, -NRc9AS(O)(=NRe9A)Rb9A, - NRc9AS(O)(=NRe9A)NRc9ARd9A, -OS(O)(=NRe9A)Rb9A, -S(O)(=NRe9A)Rb9A, - S(O)(=NRe9A)NRc9ARd9A, -C(O)NRc9AS(O)2Rb9A, -C(O)NRc9AS(O)2NRc9ARd9A, - S(O)2NRc9AC(O)Rb9A, -NRc9AS(O)NRc9AC(O)Rb9A, and -P(O)R®ARg9A, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R9Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra9A, Rc9A, and Rd9Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra9A, Rc9A, and Rd9Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc9Aand Rd9Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein54057 -0016W01 / SNV-0013W01 PATENT the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb9Ais independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb9Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re9Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R®Aand Rg9Aare independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R10is independently selected from H, oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, -CN, -ORal°, -SRal°, -NRcl0Rdl°, -NO2, -C(O)Ral°, -C(O)ORal°, - C(O)NRcl0Rdl°, -C(O)NRcl0(ORal°), -OC(O)Ral°, -OC(O)NRcl0Rdl°, -OC(O)ORal°, - OS(O)2Rbl°, -OS(O)2NRcl0Rd10, -NRcl0C(O)Ral°, -NRcl0C(O)ORal°, - NRcl0C(O)NRcl0Rdl°, -NRcl0S(O)2Rbl°, -NRcl0S(O)2NRcl0Rdl°, -NRcl0ORal°, - NRcl0S(O)Rbl°, -NRcl0S(O)NRcl0Rdl°, -S(O)Rbl°, -S(O)2Rbl°, -S(O)NRcl0Rdl°, - S(O)2NRcl0Rd10, -C(=NRel0)Ral°, -C(=NRel0)NRcl0Rdl°, -NRcl0C(=NRel0)Ral°, - NRcl0C(=NRel0)NRcl0Rd10, -NRcl0S(O)(=NRel0)Rbl°, -NRcl0S(O)(=NRel0)NRcl0Rd10, -54057 -0016W01 / SNV-0013W01 PATENTOS(O)(=NRel0)Rb10, -S(O)(=NRel0)Rbl°, -S(O)(=NRel0)NRcl0Rdl°, - C(O)NRcl0S(O)2Rbl°, -C(O)NRcl0S(O)2NRcl0Rdl°, -S(O)2NRcl0C(O)Rb10, - NRcl0S(O)NRcl0C(O)Rbl°, and -P(O)Rfl0Rgl°, wherein the Ci-6alkyl, C2.6alkenyl, C2. 6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R10are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R10Asubstituents; or, two R10, together with the atoms to which they are attached, form a C3-10 cycloalkyl, or 4-10 membered heterocycloalkyl group, wherein the C3-10 cycloalkyl and 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R10Asubstituents; each Ral°, Rcl°, and Rdl° is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ral°, Rcl°, and Rdl° are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R10Asubstituents; or, any Rcl° and Rdl° attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R10Asubstituents; each Rbl° is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-54057 -0016W01 / SNV-0013W01 PATENTCi-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rbl° are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R10Asubstituents; each Rel° is independently selected from H, OH, CN, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Rfl° and Rgl° are independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl,4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R1OAis independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, -NRcl0AS(O)NRcl0AC(O)Rbl0A, and -P(O)Rfl0ARgl0A, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered54057 -0016W01 / SNV-0013W01 PATENT heteroaryl)-Ci-4 alkyl of R10Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ral0A, Rcl0A, and Rdl0Ais independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ral0A, RCWAan(j pdioAare eac 0pp0naiiy substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any RC10Aand Rdl0Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rbl0Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rbl0Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rel0Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Rfl0Aand Rgl0Aare independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-54057 -0016W01 / SNV-0013W01 PATENT10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl; each R11is independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, - ORa11, -SRa11, -NRcl lRd11, -NO2, -C(O)Ra11, -C(O)ORa11, -C(O)NRcllRd11, - C(O)NRcl l(ORa11), -OC(O)Ra11, -OC(O)NRcl lRd11, -OC(O)ORa11, -OS(O)2Rb11, - OS(O)2NRcllRd11, -NRcl lC(O)Ra11, -NRcllC(O)ORa11, -NRcl lC(O)NRcllRd11, - NRcllS(O)2Rb11, -NRcl lS(O)2NRcllRd11, -NRcl lORa11, -NRcl lS(O)Rb11, - NRcllS(O)NRcl lRd11, -S(O)Rb11, -S(O)2Rb11, -S(O)NRcl lRd11, -S(O)2NRcllRd11, - C(=NRel l)Ra11, -C(=NRel l)NRcllRd11, -NRcl lC(=NRel l)Ra11, - NRcllC(=NRel l)NRcllRd11, -NRcl lS(O)(=NRel l)Rb11, -NRcl lS(O)(=NRel l)NRcl lRd11, - OS(O)(=NRel l)Rb11, -S(O)(=NRel l)Rb11, -S(O)(=NRell)NRcl lRd11, - C(O)NRcl lS(O)2Rbn, -C(O)NRcl lS(O)2NRcl lRd11, -S(O)2NRcllC(O)Rb11, - NRcllS(O)NRcl lC(O)Rb11, and -P(O)Rfl lRg11, wherein the Ci-6alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R11are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R11Asubstituents; or, R4and one of R11, together with the atoms to which they are attached, form a 5-10 membered heterocycloalkyl group, wherein the 5-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R11Asubstituents; or, R1and one of R11, together with the atoms to which they are attached, form a 5-10 membered heterocycloalkyl group, wherein the 5-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R11Asubstituents; or, two R11, together with the atoms to which they are attached, form a C3-10 cycloalkyl, or 4-10 membered heterocycloalkyl group, wherein the C3-10 cycloalkyl54057 -0016W01 / SNV-0013W01 PATENT and 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R11Asubstituents; each Ral 1, Rcl 1, and Rdl 1is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ral1, Rcl 1, and Rdl 1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R11Asubstituents; or, any Rcl 1and Rdl 1attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R11Asubstituents; each Rbl 1is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rbl1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R11Asubstituents; each Rel 1is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Rfl 1and Rgl 1are independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl,54057 -0016W01 / SNV-0013W01 PATENT4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R11Ais independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, - ORallA, -SRallA, -NRcl lARdl lA, -NO2, -C(O)Ral lA, -C(O)ORal lA, -C(O)NRcl lARdl lA, - C(O)NRcl lA(ORallA), -OC(O)Ral lA, -OC(O)NRcllARdl lA, -OC(O)ORal lA, - OS(O)2Rbl lA, -OS(O)2NRcllARdl lA, -NRcl lAC(O)RallA, -NRcl lAC(O)ORal lA, - NRcllAC(O)NRcl lARdllA, -NRcllAS(O)2Rbl lA, -NRcllAS(O)2NRcl lARdllA, - NRcllAORallA, -NRcllAS(O)Rbl lA, -NRcllAS(O)NRcl lARdllA, -S(O)Rbl lA, -S(O)2Rbl lA, -S(O)NRcl lARdl lA, -S(O)2NRcl lARdllA, -C(=NRel lA)Ral lA, -C(=NRellA)NRcl lARdl lA, - NRcllAC(=NRellA)RallA, -NRcl lAC(=NRel lA)NRcllARdl lA, - NRcllAS(O)(=NRel lA)RbllA, -NRcl lAS(O)(=NRellA)NRcl lARdllA, - OS(O)(=NRel lA)Rbl lA, -S(O)(=NRel lA)Rbl lA, -S(O)(=NRel lA)NRcl lARdllA, - C(O)NRcl lAS(O)2RbllA, -C(O)NRcl lAS(O)2NRcllARdl lA, -S(O)2NRcl lAC(O)Rbl lA, - NRcllAS(O)NRcllAC(O)Rbl lA, and -P(O)Rfl lARgllA, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R11Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ral lA, Rcl lA, and Rdl lAis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of RallA,54057 -0016W01 / SNV-0013W01 PATENTRC11A, and RdllAare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any RC11Aand RdllAattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rbl lAis independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of RbllAare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rel lAis independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Rfl lAand Rgl lAare independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce- 10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl; each RGis independently selected from OH, CN, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-Ci-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-3 alkylamino, di(Ci-3 alkyl)amino, thio, C1-3 alkylthio, C1-3 alkylsulfinyl, Ci- 3 alkyl sulfonyl, carbamyl, C1-3 alkylcarbamyl, di(Ci-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxy carbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di (C 1-354057 -0016W01 / SNV-0013W01 PATENT alkyl)aminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(Ci-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di (C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di(Ci-3 alkyl)aminocarbonylamino.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is N.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is C.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Y is C.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Z is O.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:X is N or C;Y is C; and Z is O.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein X1is CR5.54057 -0016W01 / SNV-0013W01 PATENT9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R5is selected from H and Ci-4 alkyl.

10. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R5is H.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein X2is CR6.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R6is selected from H and Ci-4 alkyl.

13. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R6is H.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein X3is CR7.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R7is selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R7are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R7Asubstituents.

16. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R7is selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, and 5-6 membered heteroaryl of R7are each optionally substituted with 1, 2, 3, or 4 independently selected R7Asubstituents.54057 -0016W01 / SNV-0013W01 PATENT17. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R7is selected from H, halo, Ci-6 alkyl, C3-7 cycloalkyl, phenyl, monocyclic 4-7 membered heterocycloalkyl, and spirocyclic 8-10 membered heterocycloalkyl wherein the C1-6 alkyl, C3-7 cycloalkyl, phenyl, monocyclic 4-7 membered heterocycloalkyl, and spirocyclic 8-10 membered heterocycloalkyl of R7are each optionally substituted with 1, 2, 3, or 4 independently selected R7Asubstituents.

18. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R7is selected from H, fluoro, chloro, bromo, methyl, cyclohexenyl, phenyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, 4,7- di azaspiro [2.5 ]octanyl, and 2-oxa-7-azaspiro[3.5]nonanyl, wherein the methyl, cyclohexenyl, phenyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, 4,7- di azaspiro [2.5 ]octanyl, and 2-oxa-7-azaspiro[3.5]nonanyl of R7are each optionally substituted with 1 or 2 independently selected R7Asubstituents.

19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein each R7Ais independently selected from C1-6 alkyl, 4-10 membered heterocycloalkyl, -C(O)Ra7A, -C(O)NRc7ARd7A, NRc7ARd7A, - NRc7AC(O)Ra7A, -NRc7AC(O)ORa7A, -NRc7AC(O)NRc7ARd7A, -NRc7AS(O)2Rb7A, - NRc7AS(O)2NRc7ARd7A, -NRc7AORa7A, -NRc7AS(O)Rb7A, -NRc7AS(O)NRc7ARd7A, - NRc7AC(=NRe7A)Ra7A, -NRc7AC(=NRe7A)NRc7ARd7A, -NRc7AS(O)(=NRe7A)Rb7A, - NRc7AS(O)(=NRe7A)NRc7ARd7A, and -NRc7AS(O)NRc7AC(O)Rb7A, wherein the Ci-6alkyl and 4-10 membered heterocycloalkyl of R7Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents.

20. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein each R7Ais independently selected from C1-6 alkyl, 4-7 membered heterocycloalkyl, -C(O)Ra7A, -C(O)NRc7ARd7A, and NRc7ARd7A, wherein the C1-6 alkyl and 4-7 membered heterocycloalkyl of R7Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.54057 -0016W01 / SNV-0013W01 PATENT21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein each Ra7A, Rc7A, and Rd7Ais independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of Ra7A, Rc7A, and Rd7Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents.

22. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein each Ra7A, Rc7A, and Rd7Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl of Ra7A, RC7A, and Rd7Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

23. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein each Ra7A, Rc7A, and Rd7Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, and 4-7 membered heterocycloalkyl, the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, and 4-7 membered heterocycloalkyl of Ra7A, RC7A, and Rd7Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

24. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein each Ra7A, Rc7A, and Rd7Ais independently selected from methyl, isopropyl, fluoroisopropyl, cyclopropyl, and morpholinyl, wherein the methyl, isopropyl, fluoroisopropyl, cyclopropyl, and morpholinyl of Ra7A, Rc7A, and Rd7Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

25. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, R7is selected from H, fluoro, chloro, bromo,54057 -0016W01 / SNV-0013W01 PATENT26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R1is selected from C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci- 4 alkyl, wherein the C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl- C1-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents.

27. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R1is C3-6 cycloalkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.54057 -0016W01 / SNV-0013W01 PATENT28. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R1is cyclopropyl, which is optionally substituted with 1 or 2 independently selected RGsubstituents.

29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein each RGis independently selected from CN, halo, Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, cyano-Ci-4 alkyl, HO-C1-4 alkyl, and di(Ci-3 alkyl)amino.

30. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein each RGis independently selected from CN, halo, C1-4 alkyl, C1-4 alkoxy, and di(Ci-3 alkyl)amino.

31. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein each RGis fluoro, CN, methyl, methoxy, and dimethylamino.

32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein Ring A is 5-6 membered heteroaryl.

33. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein Ring A is 5-membered heteroaryl.

34. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from pyrazolyl, imidazolyl, and triazolyl.

35. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.

36. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.54057 -0016W01 / SNV-0013W01 PATENT37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein each R3is independently selected from Ci-6 alkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, C6-io aryl-Ci-4 alkyl, -C(O)Ra3, -C(O)ORa3, -C(O)NRc3Rd3, -C(O)NRc3(ORa3), -S(O)2NRc3C(O)Rb3, -NRc3S(O)NRc3C(O)Rb3, and -P(O)RfiRg3, wherein the Ci-6alkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, and Ce-io aryl -C 1-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents.

38. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein each R3is independently selected from halo, C1-6 alkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, C6-io aryl-Ci-4 alkyl, -C(O)Ra3, -C(O)ORa3, and -C(O)NRc3Rd3, wherein the Ci-6alkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, and Ce-io aryl-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, or 4 independently selected R3Asubstituents.

39. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein each R3is independently selected from halo, Ci-6 alkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, (phenyl)-Ci-4 alkyl and -C(O)NRc3Rd3, wherein the Ci-6 alkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, and (phenyl)- C1-4 alkyl of R3are each optionally substituted with 1, 2, 3, or 4 independently selected R3Asubstituents.54057 -0016W01 / SNV-0013W01 PATENT40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein each Rc3and Rd3is independently selected from H, Ci-6 alkyl, Ci- 6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl.

41. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein each Rc3and Rd3is independently selected from H, C1-6 alkyl, Ci-6 haloalkyl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl.

42. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein each Rc3and Rd3is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl-Ci-4 alkyl, and phenyl-Ci-4 alkyl.

43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein each R3Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl.

44. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein each R3Ais independently selected from C1-6 alkyl.

45. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein each R3Ais methyl.

46. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein each R3is independently selected from methyl, ethyl, isobutyl,54057 -0016W01 / SNV-0013W01 PATENT iodo, cyclohexylmethyl, cyclohexylethyl, benzyl, methylpiperidinyl, methylpyrazolyl,47. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein n is 0.

48. The compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, wherein R2is selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents.

49. The compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, wherein R2is selected from C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)- C1-4 alkyl, wherein the C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents.

50. The compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, wherein R2is (5-6 membered heteroaryl)-Ci-4 alkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.54057 -0016W01 / SNV-0013W01 PATENT51. The compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, wherein R2is selected from pyrazolylmethyl, thiazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, and oxadiazolylmethyl, wherein the pyrazolylmethyl, thiazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, and oxadiazolylmethyl of R2are each optionally substituted with 1 or 2 independently selected R2Asubstituents.

52. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein each R2Ais independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-e alkynyl, and C1-6 haloalkyl.

53. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein each R2Ais independently selected from C1-6 alkyl and C1-6 haloalkyl.

54. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein each R2Ais independently selected from C1-4 alkyl and C1-4 haloalkyl.

55. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein each R2Ais independently selected from methyl, tert-butyl, and difluoromethyl.

56. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:= is a single or double bond; n is 0, 1, or 2;X is C or N;Y is C or N;Z is O;54057 -0016W01 / SNV-0013W01 PATENTX1is CR5;X2is CR6;X3is CR7;Ring A is phenyl or 5-6 membered heteroaryl;R1is selected from C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl, wherein the C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;R2is selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each R2Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; each R3is independently selected from C1-6 alkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, -C(O)Ra3, -C(O)ORa3, -C(O)NRc3Rd3, -C(O)NRc3(ORa3), -OC(O)Ra3, -54057 -0016W01 / SNV-0013W01 PATENTP(O)RfiRg3, wherein the Ci-6 alkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, and Ce-io aryl-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Ra3, Rc3, and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; or, any Rc3and Rd3attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group; each Rb3is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Re3is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Rfiand Rg3are independently selected from H, C1-6 alkyl, C1-6 alkoxy, Ci- 6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R3Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl;R5is selected from H and C1-4 alkyl;R6is selected from H and C1-4 alkyl;R7is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered54057 -0016W01 / SNV-0013W01 PATENT heteroaryl of R7are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R7Asubstituents; each R7Ais independently selected from Ci-6 alkyl, 4-10 membered heterocycloalkyl, -C(O)Ra7A, -C(O)NRc7ARd7A, NRc7ARd7A, -NRc7AC(O)Ra7A, - NRc7AC(O)ORa7A, -NRc7AC(O)NRc7ARd7A, -NRc7AS(O)2Rb7A, -NRc7AS(O)2NRc7ARd7A, -NRc7AORa7A, -NRc7AS(O)Rb7A, -NRc7AS(O)NRc7ARd7A, -NRc7AC(=NRe7A)Ra7A, - NRc7AC(=NRe7A)NRc7ARd7A, -NRc7AS(O)(=NRe7A)Rb7A, - NRc7AS(O)(=NRe7A)NRc7ARd7A, and -NRc7AS(O)NRc7AC(O)Rb7A, wherein the Ci-6alkyl and 4-10 membered heterocycloalkyl of R7Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra7A, Rc7A, and Rd7Ais independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; or, any Rc7Aand Rd7Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group; each Rb7Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Re7Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; and each RGis independently selected from OH, CN, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-Ci-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-3 alkylamino, di(Ci-3 alkyl)amino, thio, C1-3 alkylthio, C1-3 alkylsulfinyl, Ci- 3 alkyl sulfonyl, carbamyl, C1-3 alkylcarbamyl, di(Ci-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino,54057 -0016W01 / SNV-0013W01 PATENTC1-3 alkoxy carbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di (C 1-3 alkyl)aminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(Ci-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di (C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di(Ci-3 alkyl)aminocarbonylamino.

57. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:= is a single or double bond; n is 0, 1, or 2;X is C or N;Y is C or N;Z is O;X1is CR5;X2is CR6;X3is CR7;Ring A is phenyl or 5-6 membered heteroaryl;R1is selected from C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl, wherein the C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;R2is selected from C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents;54057 -0016W01 / SNV-0013W01 PATENT each R2Ais independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; each R3is independently selected from halo, C1-6 alkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, (phenyl)-Ci-4 alkyl, and -C(O)NRc3Rd3, wherein the C1-6 alkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, and (phenyl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, or 4 independently selected R3Asubstituents; each Rc3and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R3Ais independently selected from C1-6 alkyl;R5is selected from H and C1-4 alkyl;R6is selected from H and C1-4 alkyl;R7is selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, and 5- 6 membered heteroaryl of R7are each optionally substituted with 1, 2, 3, or 4 independently selected R7Asubstituents; each R7Ais independently selected from C1-6 alkyl, 4-7 membered heterocycloalkyl, -C(O)Ra7A, -C(O)NRc7ARd7A, and NRc7ARd7A, wherein the C1-6 alkyl and 4-7 membered heterocycloalkyl of R7Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; each Ra7A, Rc7A, and Rd7Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl of Rc7Aand Rd7Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; and each RGis independently selected from OH, CN, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-Ci-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C1-4 alkoxy, C1-4 haloalkoxy,54057 -0016W01 / SNV-0013W01 PATENT amino, C1-3 alkylamino, di(Ci-3 alkyl)amino, thio, C1-3 alkylthio, C1-3 alkylsulfinyl, Ci- 3 alkyl sulfonyl, carbamyl, C1-3 alkylcarbamyl, di(Ci-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxy carbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di (C 1-3 alkyl)aminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(Ci-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di (C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di(Ci-3 alkyl)aminocarbonylamino.

58. The compound of claim 1, wherein the compound of Formula I is a compound of Formula II:II or a pharmaceutically acceptable salt thereof.

59. The compound of claim 1, wherein the compound of Formula I is a compound of Formula III:Ill or a pharmaceutically acceptable salt thereof.

60. The compound of claim 1, wherein the compound of Formula I is a compound of Formula IV:54057 -0016W01 / SNV-0013W01 PATENTIV or a pharmaceutically acceptable salt thereof.

61. The compound of claim 1, which is selected from:9-bromo-N-methyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-3- carboxamide;9-bromo-N-(cyclopropylmethyl)-4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N- (l-methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-3- carboxamide;N-benzyl-9-bromo-4-((l -methyl- lH-pyrazol-4-yl)methyl)-7-(N-(l - methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-3- carboxamide;9-bromo-3-iodo-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l- methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-7-sulfonamide;9-bromo-4-((l -methyl- lH-pyrazol-4-yl)methyl)-N-(l -methylcy cl opropyl)-5- oxo-4, 5 -dihy droimidazof 1 , 5 -a] quinazoline-7-sulfonamide;3-iodo-4-((l -methyl-lH-pyrazol-4-yl)methyl)-N-(l -methylcy cl opropyl)-5- oxo-9-phenyl-4,5-dihydroimidazo[l,5-a]quinazoline-7-sulfonamide;9-((cyclopropyl(methyl)amino)methyl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,5-a]quinazoline-7- sulfonamide; and9-bromo-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5- oxo-4, 5-dihy droimidazof l,2-a]quinazoline-7-sulfonamide; or a pharmaceutically acceptable salt thereof.

62. The compound of claim 1, which is selected from:54057 -0016W01 / SNV-0013W01 PATENT(R)-9-(4-isobutyryl-3-methylpiperazin-l-yl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazoline-7- sulfonamide;(R)-N,N,2-trimethyl-4-(4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9- yl)piperazine-l -carboxamide;(R)-4-((l-methyl-lH-pyrazol-4-yl)methyl)-9-(3-methyl-4-(morpholine-4- carbonyl)piperazin-l-yl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5- a]quinazoline-7-sulfonamide;(R)-9-(4-( 1 -methoxy cyclopropane- 1 -carbonyl)-3 -methylpiperazin- 1 -yl)-4-(( 1 - methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide;(R)-9-(4-(2-fluoro-2-methylpropanoyl)-3 -methylpiperazin- l-yl)-4-((l-m ethyl- lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5- a]quinazoline-7-sulfonamide;(R)-9-(4-( 1 -cyanocyclopropane- 1 -carbonyl)-3 -methylpiperazin- 1 -yl)-4-(( 1 - methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide;(R)-9-(4-(3,3-difluorocyclobutane-l-carbonyl)-3-methylpiperazin-l-yl)-4-((l- methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide;9-(4-(l-methoxycyclopropane-l-carbonyl)-4,7-diazaspiro[2.5]octan-7-yl)-4- ((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide;9-(4-(cyclopropanecarbonyl)piperazin-l-yl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazoline-7- sulfonamide;N,N-dimethyl-4-(4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9- yl)piperazine-l -carboxamide;54057 -0016W01 / SNV-0013W01 PATENT4-((l -methyl- lH-pyrazol-4-yl)methyl)-N-(l-methylcy cl opropyl)-5-oxo-9-(2- oxa-7-azaspiro[3.5 ]nonan-7-yl)-4, 5 -dihy dropyrazolof 1 , 5 -a] quinazoline-7- sulfonamide;(R)-9-(4-isobutyryl-3-isopropylpiperazin-l-yl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazoline-7- sulfonamide;(R)-2-isopropyl-N,N-dimethyl-4-(4-((l-methyl-lH-pyrazol-4-yl)methyl)-7- (N-(l-methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9- yl)piperazine-l -carboxamide;(R)-9-(3 -isopropyl-4-( 1 -methoxy cyclopropane- 1 -carbonyl)piperazin- 1 -yl)-4- ((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide;9-(4-isobutyryl-3-(methoxymethyl)piperazin-l-yl)-4-((l-methyl-lH-pyrazol- 4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazoline- 7-sulfonamide;2-(methoxymethyl)-N,N-dimethyl-4-(4-((l -methyl- lH-pyrazol-4-yl)methyl)- 7-(N-(l-methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin- 9-yl)piperazine- 1 -carboxamide;9-(4-(l -methoxy cyclopropane- 1 -carbonyl)-3 -(methoxymethyl)piperazin- 1 -yl)- 4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydropyrazolo[l,5-a]quinazoline-7-sulfonamide;4-(4-((5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)- N,N-dimethylpiperazine- 1 -carboxamide;4-(4-((5-(tert-butyl)-l,2,4-oxadiazol-3-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)- N,N-dimethylpiperazine- 1 -carboxamide;4-(4-((l-(difluoromethyl)-lH-pyrazol-3-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)- N,N-dimethylpiperazine- 1 -carboxamide;54057 -0016W01 / SNV-0013W01 PATENTN,N-dimethyl-4-(7-(N-(l-methylcyclopropyl)sulfamoyl)-4-((2-methylthiazol- 5-yl)methyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)piperazine-l- carboxamide;4-(4-((3,5-dimethylisoxazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)- N,N-dimethylpiperazine- 1 -carboxamide;N,N-dimethyl-4-(7-(N-(l-methylcyclopropyl)sulfamoyl)-4-((3- methylisoxazol-4-yl)methyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9- yl)piperazine-l -carboxamide;9-(4-isobutyrylpiperazin- 1 -y l)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-N-( 1 - methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,2-a]quinazoline-7-sulfonamide;9-(4-(2-fluoro-2-methylpropanoyl)piperazin-l-yl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,2-a]quinazoline-7- sulfonamide;(R)-9-(4-isobutyryl-3-methylpiperazin-l-yl)-4-((l-methyl-lH-pyrazol-4- yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,2-a]quinazoline-7- sulfonamide;(R)-N,N,2-trimethyl-4-(4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydroimidazo[l,2-a]quinazolin-9- yl)piperazine-l -carboxamide;(R)-9-(4-( 1 -methoxy cyclopropane- 1 -carbonyl)-3 -methylpiperazin- 1 -yl)-4-(( 1 - methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydroimidazo[l,2-a]quinazoline-7-sulfonamide;(R)-9-(4-( 1 -cyanocyclopropane- 1 -carbonyl)-3 -methylpiperazin- 1 -yl)-4-(( 1 - methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydroimidazo[l,2-a]quinazoline-7-sulfonamide;(R)-9-(4-( 1 -fluorocyclopropane- 1 -carbonyl)-3 -methylpiperazin- 1 -yl)-4-(( 1 - methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydroimidazo[l,2-a]quinazoline-7-sulfonamide;(R)-9-(4-(l-(dimethylamino)cyclopropane-l-carbonyl)-3-methylpiperazin-l- yl)-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5-oxo-4,5- dihydroimidazo[l,2-a]quinazoline-7-sulfonamide;54057 -0016W01 / SNV-0013W01 PATENT4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-9-(4- morpholinocyclohex-l-en-l-yl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazoline-7- sulfonamide;N,N-dimethyl-4-(4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)-3,6- dihydropyridine- 1 (2H)-carboxamide; l-isobutyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5- oxo-4, 5-dihydroimidazo[l,2-a]quinazoline-7-sulfonamide;1 -(cyclohexylmethyl)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-N-( 1 - methylcyclopropyl)-5-oxo-4,5-dihydroimidazo[l,2-a]quinazoline-7-sulfonamide; l-benzyl-4-((l -methyl- lH-pyrazol-4-yl)methyl)-N-(l-methylcy cl opropyl)-5- oxo-4, 5-dihydroimidazo[l,2-a]quinazoline-7-sulfonamide;1 -(1 -cyclohexylethyl)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-N-( 1 - methylcyclopropyl)-5-oxo-4,5-dihydro-[l,2,4]triazolo[4,3-a]quinazoline-7- sulfonamide;9-fluoro-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-5- oxo-4, 5-dihydro-[l, 2, 4]tri azolof l,5-a]quinazoline-7-sulfonamide;3-methyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-l- (4-methylpiperazin-l-yl)-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinoline-7- sulfonamide;9-chloro-3-m ethyl -4-((l -methyl- lH-pyrazol-4-yl)methyl)-N-(l - methylcyclopropyl)-5-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]isoquinoline-7- sulfonamide;(R)-4-(3-ethyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(N-(l- methylcyclopropyl)sulfamoyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]quinazolin-9-yl)- N,N,2-trimethylpiperazine- 1 -carboxamide; and(R)-N,N,2-trimethyl-4-(3-(l-methyl-lH-pyrazol-4-yl)-4-((l-methyl-lH- pyrazol-4-yl)methyl)-7-(N-(l-methylcyclopropyl)sulfamoyl)-5-oxo-4,5- dihydropyrazolof 1 ,5 -a]quinazolin-9-yl)piperazine- 1 -carboxamide; or a pharmaceutically acceptable salt thereof.54057 -0016W01 / SNV-0013W01 PATENT63. A pharmaceutical composition, comprising a compound of any one of claims 1 to 62, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

64. A method of inhibiting an activity of poly(ADP-ribose) glycohydrolase, comprising contacting the poly(ADP-ribose) glycohydrolase with a compound of any one of claims 1 to 62, or a pharmaceutically acceptable salt thereof.

65. A method of treating a poly(ADP-ribose) glycohydrolase-mediated disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 62, or a pharmaceutically acceptable salt thereof.

66. The method of claim 65, wherein the disease or disorder is a cancer.

67. The method of claim 66, wherein the cancer is selected from skin cancer, ovarian cancer, fallopian tube cancer, gastric cancer, colorectal cancer, breast cancer, prostate cancer, uterine cancer, pancreatic cancer, lung cancer, melanoma, brain cancer, bladder cancer, head and neck cancer, sarcoma, liver cancer, bile duct cancer, kidney cancer, lymphoma, and leukemia.

68. The method of claim 66, wherein the cancer is selected from ovarian cancer, colorectal cancer, breast cancer, prostate cancer, uterine cancer, and pancreatic cancer.

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